Benzothiazole compounds and uses thereof

ABSTRACT

Disclosed are compounds of Formula (I), methods of using the compounds for inhibiting HPK1 activity and pharmaceutical compositions comprising such compounds. The compounds are useful in treating, preventing or ameliorating diseases or disorders associated with HPK1 activity such as cancer.

FIELD

The disclosure provides compounds as well as their compositions andmethods of use. The compounds modulate hematopoietic progenitor kinase 1(HPK1) activity and are useful in the treatment of various diseasesincluding cancer.

BACKGROUND

Hematopoietic progenitor kinase 1 (HPK1) originally cloned fromhematopoietic progenitor cells is a member of MAP kinase kinase kinasekinases (MAP4Ks) family, which includes MAP4K1/HPK1, MAP4K2/GCK,MAP4K3/GLK, MAP4K4/HGK, MAP4K5/KHS, and MAP4K6/MINK (Hu, M. C., et al.,Genes Dev, 1996.10 (18): p. 2251-64). HPK1 is of particular interestbecause it is predominantly expressed in hematopoietic cells such as Tcells, B cells, macrophages, dendritic cells, neutrophils, and mastcells (Hu, M. C., et al., Genes Dev, 1996. 10 (18): p. 2251-64; Kiefer,F., et al., EMBO J, 1996. 15 (24): p. 7013-25). HPK1 kinase activity hasbeen shown to be induced upon activation of T cell receptors (TCR)(Liou, J., et al., Immunity, 2000. 12 (4): p. 399-408), B cell receptors(BCR) (Liou, J., et al., Immunity, 2000. 12 (4): p. 399-408),transforming growth factor receptor (TGF-βR) (Wang, W., et al., J BiolChem, 1997. 272 (36): p. 22771-5; Zhou, G., et al., J Biol Chem, 1999.274(19): p. 13133-8), or G_(s)-coupled PGE₂ receptors (EP2 and EP4)(Ikegami, R., et al., J Immunol, 2001. 166(7): p. 4689-96). As such,HPK1 regulates diverse functions of various immune cells.

HPK1 is important in regulating the functions of various immune cellsand it has been implicated in autoimmune diseases and anti-tumorimmunity (Shui, J. W., et al., Nat Immunol, 2007. 8(1): p. 84-91; Wang,X., et al., J Biol Chem, 2012. 287(14): p. 11037-48). HPK1 knockout micewere more susceptible to the induction of experimental autoimmuneencephalomyelitis (EAE) (Shui, J. W., et al., Nat Immunol, 2007. 8(1):p. 84-91). In human, HPK1 was downregulated in peripheral bloodmononuclear cells of psoriatic arthritis patients or T cells of systemiclupus erythematosus (SLE) patients (Batliwalla, F. M., et al., Mol Med,2005. 11(1-12): p. 21-9). Those observations suggested that attenuationof HPK1 activity may contribute to autoimmunity in patients.Furthermore, HPK1 may also control anti-tumor immunity via Tcell-dependent mechanisms. In the PGE2-producing Lewis lung carcinomatumor model, the tumors developed more slowly in HPK1 knockout mice ascompared to wild-type mice (see US 2007/0087988). In addition, it wasshown that adoptive transfer of HPK1 deficient T cells was moreeffective in controlling tumor growth and metastasis than wild-type Tcells (Alzabin, S., et al., Cancer Immunol Immunother, 2010. 59(3): p.419-29). Similarly, BMDCs from HPK1 knockout mice were more efficient tomount a T cell response to eradicate Lewis lung carcinoma as compared towild-type BMIDCs (Alzabin, S., et al., J Immunol, 2009. 182(10): p.6187-94). These data, in conjunction with the restricted expression ofHPK1 in hematopoietic cells and lack of effect on the normal developmentof immune cells, suggest that HPK1 is a drug target for enhancingantitumor immunity. Accordingly, there is a need for new compounds thatmodulate HPK1 activity.

SUMMARY

The present disclosure provides, inter alia, a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein constituentvariables are defined herein.

The present disclosure further provides a pharmaceutical compositioncomprising a compound of the disclosure, or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier or excipient.

The present disclosure further provides methods of inhibiting HPK1activity, which comprises administering to an individual a compound ofthe disclosure, or a pharmaceutically acceptable salt thereof. Thepresent disclosure also provides uses of the compounds described hereinin the manufacture of a medicament for use in therapy. The presentdisclosure also provides the compounds described herein for use intherapy.

The present disclosure further provides methods of treating a disease ordisorder in a patient comprising administering to the patient atherapeutically effective amount of a compound of the disclosure, or apharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION Compounds

The present disclosure provides a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

A is N or CR^(A);

Cy^(B) is selected from C₅₋₁₀ cycloalkyl, C₆₋₁₀ aryl, and 5-6 memberedheteroaryl; wherein the 5-6 membered heteroaryl each has at least onering-forming carbon atom and 1, 2 or 3 ring-forming heteroatomsindependently selected from N, O, and S; wherein the N and S areoptionally oxidized; wherein a ring-forming carbon atom of 5-6 memberedheteroaryl is optionally substituted by oxo to form a carbonyl group;and wherein the C₅₋₁₀ cycloalkyl, C₆₋₁₀ aryl and 5-6 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁷;

R¹ is selected from Cy¹, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN,NO₂, SR^(a1), C(O)R^(b1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1),NR^(c1)C(O)NR^(c1)R^(d1), C(═NR^(e1))R^(b1), C(═NOR^(a1))R^(b1),C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), S(O)₂NR^(c1)R^(d1), andBR^(h1)R^(i1); wherein said C₂₋₆ alkenyl and C₂₋₆ alkynyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁰;

R² is selected from H, D, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, halo, CN, NO₂, OR^(f2), SR^(f2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2),NR^(j2)R^(k2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2),NR^(c2)C(O)NR^(c2)R^(d2), C(═NR^(e2))R^(b2), C(═NOR^(a2))R^(b2),C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), S(O)₂NR^(c2)R^(d2), andBR^(h2)R^(i2); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹³;

R³ is selected from H, D, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, halo, CN,NO₂, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), S(O)₂NR^(c3)R^(d3), and BR^(h3)R^(i3);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

R⁴ is selected from H, D, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, halo, CN,NO₂, OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), S(O)₂NR^(c4)R^(d4), and BR^(h4)R^(i4);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

R⁵ is selected from H, D, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, halo, CN, NO₂, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)OR^(a5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)S(O)R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5),S(O)₂NR^(c5)R^(d5), and BR^(h5)R^(i5); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R^(g);

R⁶ is selected from H, D, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, CN, NO₂, OR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6),OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)C(O)R^(b6), NR^(c6)C(O)OR^(a6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)S(O)R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6), S(O)₂R^(b6),S(O)₂NR^(c6)R^(d6), and BR^(h6)R^(i6); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R^(g);

each R⁷ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, NO₂, OR^(a7), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7),C(O)OR^(a7), OC(O)R^(b7), OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7),NR^(c7)C(O)R^(b7), NR^(c7)C(O)OR^(a7), NR^(c7)C(O)NR^(c7)R^(d7),C(═NR^(e7))R^(b7), C(═NOR^(a7))R^(b7), C(═NR^(e7))NR^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c7)R^(d7), NR^(c7)S(O)R^(b7), NR^(c7)S(O)₂R^(b7),NR^(c7)S(O)₂NR^(c7)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7), S(O)₂R^(b7),S(O)₂NR^(c7)R^(d7), and BR^(h7)R^(i7); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene,4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene,and 5-10 membered heteroaryl-C₁₋₃ alkylene are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR⁸;

each R⁸ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, OR^(a8), SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8),NR^(c8)R^(d8), NR^(c8)C(O)R^(b8), NR^(c8)C(O)OR^(a8), NR^(c8)S(O)R^(b8),NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), S(O)R^(b8),S(O)NR^(c8)R^(d8), S(O)₂R^(b8), S(O)₂NR^(c8)R^(d8), and BR^(h8)R^(i8);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, and 5-10 membered heteroaryl-C₁₋₃alkylene are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁹;

each R⁹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR^(a9),SR^(a9), C(O)R^(b9), C(O)NR^(c9)R^(d9), C(O)OR^(a9), NR^(c9)R^(d9),NR^(c9)C(O)R^(b9), NR^(c9)C(O)OR^(a9), NR^(c9)S(O)R^(b9),NR^(c9)S(O)₂R^(b9), NR^(c9)S(O)₂NR^(c9)R^(d9), S(O)R^(b9),S(O)NR^(c9)R^(d9), S(O)₂R^(b9), and S(O)₂NR^(c9)R^(d9); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6membered heteroaryl and 4-7 membered heterocycloalkyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

R^(A) is selected from H, D, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, halo, CN, NO₂, OR^(a14), SR^(a14), C(O)R^(b14),C(O)NR^(c14)R^(d14), C(O)OR^(a14), OC(O)R^(b14), OC(O)NR^(c14)R^(d14),NR^(c14)R^(d14), NR^(c14)C(O)R^(b14), NR^(c14)C(O)OR^(a14),NR^(c14)C(O)NR^(c14)R^(d14), NR^(c14)S(O)R^(b14), NR^(c14)S(O)₂R^(b14),NR^(c14)S(O)₂NR^(c14)R^(d14), S(O)R^(b14), S(O)NR^(c14)R^(d14),S(O)₂R^(b14), S(O)₂NR^(c14)R^(d14), and BR^(h14)R^(i14); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(g);

Cy¹ is selected from C₃₋₁₂ cycloalkyl, 4-12 membered heterocycloalkyl,C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein the 4-12 memberedheterocycloalkyl and 5-10 membered heteroaryl each has at least onering-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatomsindependently selected from N, O, and S; wherein the N and S areoptionally oxidized; wherein a ring-forming carbon atom of 5-10 memberedheteroaryl and 4-12 membered heterocycloalkyl is optionally substitutedby oxo to form a carbonyl group; and wherein said C₃₋₁₂ cycloalkyl, 4-12membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹⁰;

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, NO₂, OR^(a10), SR^(a10), C(O)R^(b10), C(O)NR^(c10)R^(d10),C(O)OR^(a10), OC(O)R^(b10), OC(O)NR^(c10)R^(d10), NR^(c10)R^(d10),NR^(c10)C(O)R^(b10), NR^(c10)C(O)OR^(a10), NR^(c10)C(O)NR^(c10)R^(d10),C(═NR^(e10))R^(b10), C(═NOR^(a10))R^(b10), C(═NR^(e10))NR^(c10)R^(d10),NR^(c10)C(═NR^(e10))NR^(c10)R^(d10), NR^(c10)S(O)R^(b10),NR^(c10)S(O)₂R^(b10), NR^(c10)S(O)₂NR^(c10)R^(d10), S(O)R^(b10),S(O)NR^(c10)R^(d10), S(O)₂R^(b10), S(O)₂NR^(c10)R^(d10), andBR^(h10)R^(i10); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, OR^(a11), SR^(a11), C(O)R^(b11), C(O)NR^(c11)R^(d11),C(O)OR^(a11), NR^(c11)R^(d11), NR^(c11)C(O)R^(b11),NR^(c11)C(O)OR^(a11), NR^(c11)S(O)R^(b11), NR^(c11)S(O)₂R^(b11),NR^(c11)S(O)₂NR^(c11)R^(d11), S(O)R^(b11), S(O)NR^(c11)R^(d11),S(O)₂R^(b11), S(O)₂NR^(c11)R^(d11), and BR^(h11)R^(i11); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹²;

each R¹² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR^(a12),SR^(a12), C(O)R^(b12), C(O)NR^(c12)R^(d12), C(O)OR^(a12),NR^(c12)R^(d12), NR^(c12)C(O)R^(b12), NR^(c12)C(O)OR^(a12),NR^(c12)S(O)R^(b12), NR^(c12)S(O)₂R^(b12), NR^(c12)S(O)₂NR^(c12)R^(d12),S(O)R^(b12), S(O)NR^(c12)R^(d12), S(O)₂R^(b12), S(O)₂NR^(c12)R^(d12),and BR^(h12)R^(i12); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, and 4-7membered heterocycloalkyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R^(g);

each R¹³ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, halo, D, CN, NO₂, OR^(a13), SR^(a13),C(O)R^(b13), C(O)NR^(c13)R^(d13), C(O)OR^(a13), OC(O)R^(b13),OC(O)NR^(c13)R^(d13), NR^(c13)R^(d13), NR^(c13)C(O)R^(b13),NR^(c13)C(O)OR^(a13), NR^(c13)C(O)NR^(c13)R^(d13), C(═NR^(e13))R^(b13),C(═NOR^(a13))R^(b13), C(═NR^(e13))NR^(c13)R^(d13),NR^(c13)C(═NR^(e13))NR^(c13)R^(d13), NR^(c13)S(O)R^(b13),NR^(c13)S(O)₂R^(b13), NR^(c13)S(O)₂NR^(c13)R^(d13), S(O)R^(b13),S(O)NR^(c13)R^(d13), S(O)₂R^(b13), S(O)₂NR^(c13)R^(d13), andBR^(h13)R^(i13); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl, are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g2);

each R^(a1), R^(c1), and R^(d1) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10 memberedheteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹⁰;

or any R^(c1) and R^(d1) attached to the same N atom, together with theN atom to which they are attached, form a 4-10 membered heterocycloalkylgroup optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹⁰;

each R^(b1) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁰;

each R^(e1) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl,aminosulfonyl, C₁₋₆ alkylaminosulfonyl, and di(C₁₋₆ alkyl)aminosulfonyl;

each R^(h1) and R^(i1) is independently selected from OH and C₁₋₆alkoxy;

or any R^(h1) and R^(i1) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3,or 4 substituents independently selected from C₁₋₆ alkyl;

each R^(a2), R^(c2), and R^(d2) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10 memberedheteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

or any R^(c2) and R^(d2) attached to the same N atom, together with theN atom to which they are attached, form a 4-10 membered heterocycloalkylgroup optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g);

each R^(b2) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

each R^(f2), R^(f2), and R^(k2) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g2);

each R^(e2) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl,aminosulfonyl, C₁₋₆ alkylaminosulfonyl, and di(C₁₋₆ alkyl)aminosulfonyl;

each R^(h2) and R^(i2) is independently selected from OH and C₁₋₆alkoxy;

or any R^(h2) and R^(i2) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3,or 4 substituents independently selected from C₁₋₆ alkyl;

each R^(a3), R^(c3), and R^(d3) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(b3) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R^(h3) and R^(i3) is independently selected from OH and C₁₋₆alkoxy;

or any R^(h3) and R^(i3) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3,or 4 substituents independently selected from C₁₋₆ alkyl;

each R^(a4), R^(c4), and R^(d4) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(b4) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R^(h4) and R^(i4) is independently selected from OH and C₁₋₆alkoxy;

or any R^(h4) and R^(i4) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3,or 4 substituents independently selected from C₁₋₆ alkyl; each R^(a5) isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g);

each R^(c5) and R^(d5) is independently selected from C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R^(g);

each R^(b5) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R^(h5) and R^(i5) is independently selected from OH and C₁₋₆alkoxy;

or any R^(h5) and R^(i5) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3,or 4 substituents independently selected from C₁₋₆ alkyl;

each R^(a6), R^(c6), and R^(d6) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(b6) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R^(h6) and R^(i6) is independently selected from OH and C₁₋₆alkoxy;

or any R^(h6) and R^(i6) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3,or 4 substituents independently selected from C₁₋₆ alkyl;

each R^(a7), R^(c7), and R^(d7) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10 memberedheteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁸;

or any R^(c7) and R^(d7) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁸;

each R^(b7) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R⁸;

each R^(e7) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl,aminosulfonyl, C₁₋₆ alkylaminosulfonyl, and di(C₁₋₆ alkyl)aminosulfonyl;

each R^(h7) and R^(i7) is independently selected from OH and C₁₋₆alkoxy;

or any R^(h7) and R^(i7) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3,or 4 substituents independently selected from C₁₋₆ alkyl;

each R^(a8), R^(c8), and R^(d8) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl;wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁹;

or any R^(c8) and R^(d8) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R⁹;

each R^(b8) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl, and 4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkylC₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl, and 4-7 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR⁹;

each R^(h8) and R^(i8) is independently selected from OH and C₁₋₆alkoxy;

or any R^(h8) and R^(i8) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3,or 4 substituents independently selected from C₁₋₆ alkyl;

each R^(a9), R^(c9), and R^(d9) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(b9) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R^(a10), R^(c10), and R^(d10) is independently selected from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,and 5-10 membered heteroaryl are each optionally substituted with 1, 2,3, or 4 substituents independently selected from R¹¹;

or any R^(c10) and R^(d10) attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹;

each R^(b10) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹¹;

each R^(e10) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl,aminosulfonyl, C₁₋₆ alkylaminosulfonyl, and di(C₁₋₆ alkyl)aminosulfonyl;

each R^(h10) and R^(i10) is independently selected from OH and C₁₋₆alkoxy;

or any R^(h10) and R^(i10) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3,or 4 substituents independently selected from C₁₋₆ alkyl;

each R^(a11), R^(c11), and R^(d11) is independently selected from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl;wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹²;

or any R^(c11) and R^(d11) attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R¹²;

each R^(b11) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl, and 4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkylC₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl, and 4-7 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹²;

each R^(h11) and R^(i11) is independently selected from OH and C₁₋₆alkoxy;

or any R^(h11) and R^(i11) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3,or 4 substituents independently selected from C₁₋₆ alkyl;

each R^(a12), R^(c12) and R^(d12) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(b12) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R^(h12) and R^(i12) is independently selected from OH and C₁₋₆alkoxy;

or any R^(h12) and R^(i12) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3,or 4 substituents independently selected from C₁₋₆ alkyl;

each R^(a13), R^(c13), and R^(d13) is independently selected from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,and 5-10 membered heteroaryl are each optionally substituted with 1, 2,3, or 4 substituents independently selected from R^(g);

each R^(b13) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

each R^(e13) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl,aminosulfonyl, C₁₋₆ alkylaminosulfonyl, and di(C₁₋₆ alkyl)aminosulfonyl;

each R^(h13) and R^(i13) is independently selected from OH and C₁₋₆alkoxy;

or any R^(h13) and R^(i13) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3,or 4 substituents independently selected from C₁₋₆ alkyl;

each R^(a14), R^(c14) and R^(d14) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(b14) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R^(h14) and R^(i14) is independently selected from OH and C₁₋₆alkoxy;

or any R^(h14) and R^(i14) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3,or 4 substituents independently selected from C₁₋₆ alkyl;

each R^(g) is independently selected from OH, NO₂, CN, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkyl-C₁₋₂ alkylene, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₃ alkoxy-C₁₋₃alkyl, C₁₋₃ alkoxy-C₁₋₃ alkoxy, HO—C₁₋₃ alkoxy, HO—C₁₋₃ alkyl,cyano-C₁₋₃ alkyl, H₂N—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl,carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino; and

each R^(g2) is independently selected from OH, NO₂, CN, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkoxy, HO—C₁₋₃alkoxy, HO—C₁₋₃ alkyl, cyano-C₁₋₃ alkyl, H₂N—C₁₋₃ alkyl, amino, C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkylaminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino.

In some embodiments, A is N. In some embodiments, A is CR^(A). R^(A) canbe selected from H, D, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, halo, CN. In some embodiments, R^(A) is selected from H, D,C₁₋₆ alkyl, C₁₋₆ haloalkyl, and halo.

In some embodiments, Cy^(B) is selected from 5-6 membered heteroaryl andC₆₋₁₀ aryl; wherein the C₅₋₁₀ cycloalkyl and C₆₋₁₀ aryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R⁷.

In some embodiments, Cy^(B) is C₆₋₁₀ aryl optionally substituted with 1,2, or 3 substituents independently selected from R⁷.

In some embodiments, Cy^(B) is phenyl optionally substituted with 1, 2,or 3 substituents independently selected from R⁷.

In some embodiments, each R⁷ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo,D, CN, OR^(a7), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7),NR^(c7)R^(d7), NR^(c7)C(O)R^(b7), and NR^(c7)C(O)OR^(a7), wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R⁸.

In some embodiments, each R⁷ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, 5-6 membered heteroaryl, halo, CN, OR^(a7), andC(O)NR^(c7)R^(d7) wherein said C₁₋₆ alkyl and 5-6 membered heteroarylare each optionally substituted with 1, 2, or 3 substituentsindependently selected from R⁸.

In some embodiments, Cy^(B) is phenyl substituted with 1, 2, or 3substituents selected from F, CN, OCH₃, CH₃, CD₃, CF₃, C(O)NH₂, and1-methyl-1H-pyrazol-4-yl.

In some embodiments, R¹ is selected from Cy¹, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, CN, SR^(a1), C(O)R^(b1), C(O)OR^(a1),NR^(c1)R^(d1), and NR^(c1)C(O)R^(b1); wherein said C₂₋₆ alkenyl and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹⁰.

In some embodiments, R¹ is selected from Cy¹ and NR^(c1)R^(d1).

In some embodiments, R¹ is Cy¹.

In some embodiments, Cy¹ is selected from 4-12 membered heterocycloalkyland C₆₋₁₀ aryl; wherein the 4-12 membered heterocycloalkyl has at leastone ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatomsindependently selected from N, O, and S; wherein the N and S areoptionally oxidized; wherein a ring-forming carbon atom of 4-12 memberedheterocycloalkyl is optionally substituted by oxo to form a carbonylgroup; and wherein the 4-12 membered heterocycloalkyl and C₆₋₁₀ aryl areeach optionally substituted with 1, 2, or 3 substituents independentlyselected from R¹⁰.

In some embodiments, Cy¹ is 4-10 membered heterocycloalkyl; wherein the4-10 membered heterocycloalkyl has at least one ring-forming carbon atomand 1, 2, 3, or 4 ring-forming heteroatoms independently selected fromN, O, and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of 4-10 membered heterocycloalkyl is optionallysubstituted by oxo to form a carbonyl group; and wherein the 4-10membered heterocycloalkyl is optionally substituted with 1, 2, or 3substituents independently selected from R¹⁰.

In some embodiments, Cy¹ is 5-9 membered heterocycloalkyl; wherein the5-9 membered heterocycloalkyl has at least one ring-forming carbon atomand 1, 2, or 3 ring-forming heteroatoms independently selected from Nand O; wherein the N is optionally oxidized; wherein a ring-formingcarbon atom of 5-9 membered heterocycloalkyl is optionally substitutedby oxo to form a carbonyl group; and wherein the 5-9 memberedheterocycloalkyl is optionally substituted with 1, 2, or 3 substituentsindependently selected from R¹⁰.

In some embodiments, Cy¹ is selected from pyrrolidinyl, morpholino,oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl,octahydro-1H-pyrrolo[2,3-c]pyridinyl, and2,5-diazabicyclo[2.2.2]octanyl, wherein said pyrrolidinyl, morpholinyl,oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl,octahydro-1H-pyrrolo[2,3-c]pyridinyl, and 2,5-diazabicyclo[2.2.2]octanylare each optionally substituted with 1, 2, or 3 substituentsindependently selected from R¹⁰.

In some embodiments, each R¹⁰ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo,D, CN, OR^(a10), SR^(a10), C(O)R^(b10), C(O)NR^(c10)R^(d10),NR^(c10)R^(d10), NR^(c10)C(O)R^(b10), NR^(c10)C(O)OR^(a10), andNR^(c10)S(O)₂R^(b10); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,and 5-10 membered heteroaryl are each optionally substituted with 1, 2,or 3 substituents independently selected from R¹¹.

In some embodiments, each R¹⁰ is independently selected from C₁₋₆ alkyl,4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, haloC(O)R^(b10), NR^(c10)R^(d10), NR^(c10)C(O)R^(b10), andNR^(c10)S(O)₂R^(b10) wherein said C₁₋₆ alkyl and 5-10 membered heteroaylare each optionally substituted with 1 or 2 substituents independentlyselected from R¹¹.

In some embodiments, each R¹¹ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, D, CN, OR^(a11), andNR^(c11)R^(d11).

In some embodiments, each R¹¹ is independently selected from C₁₋₆ alkyl,OR^(a11), and NR^(c11)R^(d11).

In some embodiments, R¹ is NR^(c1)R^(d1).

In some embodiments, R¹ is selected from 3-aminopyrrolidin-1-yl,2-(aminomethyl)pyrrolidin-1-yl,4-amino-2-(hydroxymethyl)pyrrolidin-1-yl,2-(hydroxymethyl)-4-(isopropylamino)pyrrolidin-1-yl,2-(hydroxymethyl)-4-(tetrahydro-2H-pyran-4-ylamino)pyrrolidin-1-yl,4-acetamido-2-(hydroxymethyl)pyrrolidin-1-yl,2-(hydroxymethyl)-4-(methylsulfonamido)pyrrolidin-1-yl,2-oxa-5-azabicyclo[2.2.1]heptan-5-yl,methyl((l-methylpyrrolidin-3-yl)methyl)amino,2,5-diazabicyclo[2.2.1]heptan-2-yl, 3-(aminomethyl)morpholino,methyl(piperidin-3-yl)amino, octahydro-1H-pyrrolo[2,3-c]pyridin-1-yl,3-(pyridin-2-yl)pyrrolidin-1-yl,4,4-difluoro-2-(hydroxymethyl)pyrrolidin-1-yl, and2,5-diazabicyclo[2.2.2]octan-2-yl.

In some embodiments, R² is selected from H, D, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, CN, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), andS(O)₂NR^(c2)R^(d2); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl are each optionally substituted with 1, 2, or 3 substituentsindependently selected from R¹³.

In some embodiments, R² is C₁₋₆ alkyl optionally substituted with 1, 2,or 3 substituents independently selected from R¹³.

In some embodiments, each R¹³ is independently selected from halo, D,CN, OR^(a13), C(O)R^(b13), C(O)NR^(c13)R^(d13), NR^(c13)R^(d13), andNR^(c13)C(O)R^(b13).

In some embodiments, each R¹³ is independently selected from OR^(a13)and NR^(c13)R^(d13).

In some embodiments, R² is selected from CH₃, CH₂CH₃, CH₂OCH₃,CH₂CH₂OCH₃, CH(CH₃)₂, and CH₂N(CH₃)₂.

In some embodiments, R³ is selected from H, D, C₁₋₆ alkyl, C₁₋₆haloalkyl, halo, and CN.

In some embodiments, R³ is selected from H, C₁₋₆ alkyl, halo, and CN.

In some embodiments, R³ is H.

In some embodiments, R⁴ is selected from H, D, C₁₋₆ alkyl, C₁₋₆haloalkyl, halo, and CN.

In some embodiments, R⁴ is H.

In some embodiments, R⁵ is selected from H, D, C₁₋₆ alkyl, C₁₋₆haloalkyl, halo, and CN.

In some embodiments, R⁵ is H.

In some embodiments, R⁶ is selected from H, D, C₁₋₆ alkyl, C₁₋₆haloalkyl, and CN.

In some embodiments, R⁶ is H.

In some embodiment, R³ is selected from H, C₁₋₆ alkyl, halo, and CN; R⁴is H; R⁵ is H; and R⁶ is H.

In some embodiments, provided herein is a compound of Formula II:

or a pharmaceutically acceptable salt thereof, wherein constituentvariables are defined herein.

In some embodiments, provided herein is a compound of Formula III:

or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, or 3,and remaining constituent variables are defined herein.

In some embodiments, provided herein is a compound of Formula IIIa:

or a pharmaceutically acceptable salt thereof, wherein constituentvariables are defined herein.

In some embodiments, provided herein is a compound of Formula IIIb:

or a pharmaceutically acceptable salt thereof, wherein constituentvariables are defined herein.

In some embodiments, provided herein is a compound of Formula IIIc:

or a pharmaceutically acceptable salt thereof, wherein constituentvariables are defined herein.

In some embodiments, provided herein is a compound of Formula IV:

or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, or 3,and remaining constituent variables are defined herein.

In some embodiments, provided herein is a compound of Formula V:

or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, or 3,and remaining constituent variables are defined herein.

In some embodiments, the compound is a compound of Formula I, or apharmaceutically acceptable salt thereof, wherein:

A is N or CR^(A);

Cy^(B) is selected from C₆₋₁₀ aryl optionally substituted with 1, 2, 3or 4 substituents independently selected from R⁷;

R¹ is selected from Cy¹ and NR^(c1)R^(d1);

R² is C₁₋₆ alkyl optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹³;

R³ is selected from H, C₁₋₆ alkyl, halo and CN;

R⁴ is H;

R⁵ is H;

R⁶ is H;

each R⁷ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, 5-10membered heteroaryl, halo, D, CN, OR^(a7), SR^(a7), C(O)NR^(c7)R^(d7),NR^(c7)R^(d7), and NR^(c7)C(O)R^(b7); wherein said C₁₋₆ alkyl and 5-10membered heteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁸;

each R⁸ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo,D, CN, OR^(a8), and NR^(c8)R^(d8);

R^(A) is selected from H, D, halo, and CN;

Cy¹ is selected from 4-12 membered heterocycloalkyl, and 5-10 memberedheteroaryl; wherein the 4-12 membered heterocycloalkyl and 5-10 memberedheteroaryl each has at least one ring-forming carbon atom and 1, 2, 3,or 4 ring-forming heteroatoms independently selected from N, O, and S;wherein the N and S are optionally oxidized; wherein a ring-formingcarbon atom of 5-10 membered heteroaryl and 4-12 memberedheterocycloalkyl is optionally substituted by oxo to form a carbonylgroup; and wherein the 4-12 membered heterocycloalkyl, and 5-10 memberedheteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹⁰;

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, halo, D, CN, OR^(a10), SR^(a10),C(O)NR^(c10)R^(d10) NR^(c10)R^(d10), NR^(c10)C(O)R^(b10), andNR^(c10)S(O)₂R^(b10); wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, and C₆₋₁₀ aryl, 5-10 membered heteroaryl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, D, CN, OR^(a11) and NR^(c11)R^(d11);

each R¹³ is independently selected from halo, D, CN, OR^(a13), andNR^(c13)R^(d13);

each R^(c1) and R^(d1) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl and 4-10 membered heterocycloalkyl;wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl and 4-10 memberedheterocycloalkyl, are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹⁰;

or any R^(c1) and R^(d1) attached to the same N atom, together with theN atom to which they are attached, form a 4-10 membered heterocycloalkylgroup optionally substituted with 1, 2, 3 or 4 substituentsindependently selected from R¹⁰;

each R^(a7), R^(c7) and R^(d7) is independently selected from H and C₁₋₆alkyl; wherein said C₁₋₆ alkyl, is optionally substituted with 1, 2, 3,or 4 substituents independently selected from R⁸; each R^(a8), R^(c8)and R^(d8) is independently selected from H and C₁₋₆ alkyl;

each R^(a10), R^(c10), and R^(d10) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl; wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, and 4-10membered heterocycloalkyl, are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹¹;

or any R^(c10) and R^(d10) attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹;

each R^(b10) is independently selected from C₁₋₆ alkyl;

each R^(a11), R^(c11), and R^(d11) is independently selected from H andC₁₋₆ alkyl;

each R^(a13), R^(c13), and R^(d13) is independently selected from H andC₁₋₆ alkyl; and

each R^(g) is independently selected from OH, CN, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, amino, C₁₋₆ alkylamino, anddi(C₁₋₆ alkyl)amino.

In some embodiments, the compound is a compound of Formula I, or apharmaceutically acceptable salt thereof, wherein:

A is N or CR^(A);

Cy^(B) is selected from C₆₋₁₀ aryl optionally substituted with 1, 2, 3or 4 substituents independently selected from R⁷;

R¹ is selected from Cy¹ and NR^(c1)R^(d1);

R² is C₁₋₆ alkyl optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹³;

R³ and R⁴ are each independently selected from H, D, C₁₋₆ alkyl, C₁₋₆haloalkyl, halo, and CN; wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(g);

R⁵ is selected from H, D, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, and CN;

R⁶ is selected from H, D, C₁₋₆ alkyl, C₁₋₆ haloalkyl, and CN;

each R⁷ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, 5-10membered heteroaryl, halo, D, CN, OR^(a7), SR^(a7), C(O)NR^(c7)R^(d7),NR^(c7)R^(d7), and NR^(c7)C(O)R^(b7); wherein said C₁₋₆ alkyl and 5-10membered heteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁸;

each R⁸ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo,D, CN, OR^(a8), and NR^(c8)R^(d8);

R^(A) is selected from H, D, halo, and CN;

Cy¹ is selected from 4-12 membered heterocycloalkyl, and 5-10 memberedheteroaryl; wherein the 4-12 membered heterocycloalkyl and 5-10 memberedheteroaryl each has at least one ring-forming carbon atom and 1, 2, 3,or 4 ring-forming heteroatoms independently selected from N, O, and S;wherein the N and S are optionally oxidized; wherein a ring-formingcarbon atom of 5-10 membered heteroaryl and 4-12 memberedheterocycloalkyl is optionally substituted by oxo to form a carbonylgroup; and wherein the 4-12 membered heterocycloalkyl, and 5-10 memberedheteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹⁰;

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, halo, D, CN, OR^(a10), SR^(a10),C(O)NR^(c10)R^(d10) NR^(c10)R^(d10), NR^(c10)C(O)R^(b10), andNR^(c10)S(O)₂R^(b10); wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, and C₆₋₁₀ aryl, 5-10 membered heteroaryl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, D, CN, OR^(a11) and NR^(c11)R^(d11);

each R¹³ is independently selected from halo, D, CN, OR^(a13), andNR^(c13)R^(d13);

each R^(c1) and R^(d1) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl and 4-10 membered heterocycloalkyl;wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl and 4-10 memberedheterocycloalkyl, are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹⁰;

or any R^(c1) and R^(d1) attached to the same N atom, together with theN atom to which they are attached, form a 4-10 membered heterocycloalkylgroup optionally substituted with 1, 2, 3 or 4 substituentsindependently selected from R¹⁰;

each R^(a7), R^(c7) and R^(d7) is independently selected from H and C₁₋₆alkyl; wherein said C₁₋₆ alkyl, is optionally substituted with 1, 2, 3,or 4 substituents independently selected from R⁸;

each R^(a8), R^(c8) and R^(d8) is independently selected from H and C₁₋₆alkyl;

each R^(a10), R^(c10), and R^(d10) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl; wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, and 4-10membered heterocycloalkyl, are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹¹;

or any R^(c10) and R^(d10) attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹;

each R^(b10) is independently selected from C₁₋₆ alkyl;

each R^(a11), R^(c11), and R^(d11) is independently selected from H andC₁₋₆ alkyl;

each R^(a13), R^(c13), and R^(d13) is independently selected from H andC₁₋₆ alkyl; and

each R^(g) is independently selected from OH, CN, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, amino, C₁₋₆ alkylamino, anddi(C₁₋₆ alkyl)amino.

In some embodiments, the compound is a compound of Formula I, or apharmaceutically acceptable salt thereof, wherein:

A is N;

Cy^(B) is selected from C₆₋₁₀ aryl optionally substituted with 1, 2, 3or 4 substituents independently selected from R⁷;

R¹ is selected from Cy¹, and NR^(c1)R^(d1);

R² is C₁₋₆ alkyl optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹³;

R³ and R⁴ are each independently selected from H, D, C₁₋₆ alkyl, C₁₋₆haloalkyl, halo and CN;

R⁵ is H;

R⁶ is H;

each R⁷ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, 5-10membered heteroaryl, halo, D, CN, OR^(a7), C(O)NR^(c7)R^(d7) andNR^(c7)R^(d7); wherein said C₁₋₆ alkyl and 5-10 membered heteroaryl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁸;

each R⁸ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo,D, CN, OR^(a8), and NR^(c8)R^(d8);

Cy¹ is selected from 4-12 membered heterocycloalkyl; wherein the 4-12membered heterocycloalkyl has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom is optionally substituted by oxo to form acarbonyl group; and wherein the 4-12 membered heterocycloalkyl isoptionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹⁰;

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, 4-10membered heterocycloalkyl, 5-10 membered heteroaryl, halo, D, CN,OR^(a1), C(O)NR^(c10)R^(d10) NR^(c10)R^(d10), NR^(c10)C(O)R^(b10), andNR^(c10)S(O)₂R^(b10); wherein said C₁₋₆ alkyl, 4-10 memberedheterocycloalkyl, and 5-10 membered heteroaryl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, D, CN, OR^(a11), and NR^(c11)R^(d11);

each R¹³ is independently selected from halo, D, CN, OR^(a13), andNR^(c13)R^(d13);

each R^(c1) and R^(d1) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, and 4-10 membered heterocycloalkyl; wherein said C₁₋₆alkyl, and 4-10 membered heterocycloalkyl, are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹⁰;

each R^(a7), R^(c7), and R^(d7) is independently selected from H andC₁₋₆ alkyl; wherein said C₁₋₆ alkyl is optionally substituted with 1, 2,3, or 4 substituents independently selected from R⁸;

each R^(a8), R^(c8), and R^(d8) is independently selected from H andC₁₋₆ alkyl;

each R^(a10), R^(c10), and R^(d10) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, and 4-10 membered heterocycloalkyl; whereinsaid C₁₋₆ alkyl and 4-10 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹¹;

or any R^(c10) and R^(d10) attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹;

each R^(b10) is independently selected from C₁₋₆ alkyl;

each R^(a11), R^(c11), and R^(d11) is independently selected from H andC₁₋₆ alkyl; and

each R^(a13), R^(c13), and R^(d13) is independently selected from H andC₁₋₆ alkyl.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment (while theembodiments are intended to be combined as if written in multiplydependent form). Conversely, various features of the invention whichare, for brevity, described in the context of a single embodiment, canalso be provided separately or in any suitable subcombination. Thus, itis contemplated as features described as embodiments of the compounds ofFormula (I) can be combined in any suitable combination.

At various places in the present specification, certain features of thecompounds are disclosed in groups or in ranges. It is specificallyintended that such a disclosure include each and every individualsubcombination of the members of such groups and ranges. For example,the term “C₁₋₆ alkyl” is specifically intended to individually disclose(without limitation) methyl, ethyl, C₃ alkyl, C₄ alkyl, C₅ alkyl andC₁₋₆ alkyl.

The term “n-membered”, where n is an integer, typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

At various places in the present specification, variables definingdivalent linking groups may be described. It is specifically intendedthat each linking substituent include both the forward and backwardforms of the linking substituent. For example, —NR(CR′R″)_(n)— includesboth —NR(CR′R″)_(n)— and —(CR′R″)_(n)NR— and is intended to discloseeach of the forms individually. Where the structure requires a linkinggroup, the Markush variables listed for that group are understood to belinking groups. For example, if the structure requires a linking groupand the Markush group definition for that variable lists “alkyl” or“aryl” then it is understood that the “alkyl” or “aryl” represents alinking alkylene group or arylene group, respectively.

The term “substituted” means that an atom or group of atoms formallyreplaces hydrogen as a “substituent” attached to another group. The term“substituted”, unless otherwise indicated, refers to any level ofsubstitution, e.g., mono-, di-, tri-, tetra- or penta-substitution,where such substitution is permitted. The substituents are independentlyselected, and substitution may be at any chemically accessible position.It is to be understood that substitution at a given atom is limited byvalency. It is to be understood that substitution at a given atomresults in a chemically stable molecule. The phrase “optionallysubstituted” means unsubstituted or substituted. The term “substituted”means that a hydrogen atom is removed and replaced by a substituent. Asingle divalent substituent, e.g., oxo, can replace two hydrogen atoms.

The term “C_(n-m)” indicates a range which includes the endpoints,wherein n and m are integers and indicate the number of carbons.Examples include C₁₋₄, C₁₋₆ and the like.

The term “alkyl” employed alone or in combination with other terms,refers to a saturated hydrocarbon group that may be straight-chained orbranched. The term “C_(n-m) alkyl”, refers to an alkyl group having n tom carbon atoms. An alkyl group formally corresponds to an alkane withone C—H bond replaced by the point of attachment of the alkyl group tothe remainder of the compound. In some embodiments, the alkyl groupcontains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3carbon atoms, or 1 to 2 carbon atoms. Examples of alkyl moietiesinclude, but are not limited to, chemical groups such as methyl, ethyl,n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higherhomologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl,1,2,2-trimethylpropyl and the like.

The term “alkenyl” employed alone or in combination with other terms,refers to a straight-chain or branched hydrocarbon group correspondingto an alkyl group having one or more double carbon-carbon bonds. Analkenyl group formally corresponds to an alkene with one C—H bondreplaced by the point of attachment of the alkenyl group to theremainder of the compound. The term “C_(n-m) alkenyl” refers to analkenyl group having n to m carbons. In some embodiments, the alkenylmoiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Example alkenylgroups include, but are not limited to, ethenyl, n-propenyl,isopropenyl, n-butenyl, sec-butenyl and the like.

The term “alkynyl” employed alone or in combination with other terms,refers to a straight-chain or branched hydrocarbon group correspondingto an alkyl group having one or more triple carbon-carbon bonds. Analkynyl group formally corresponds to an alkyne with one C—H bondreplaced by the point of attachment of the alkyl group to the remainderof the compound. The term “C_(n-m) alkynyl” refers to an alkynyl grouphaving n to m carbons. Example alkynyl groups include, but are notlimited to, ethynyl, propyn-1-yl, propyn-2-yl and the like. In someembodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3carbon atoms.

The term “alkylene”, employed alone or in combination with other terms,refers to a divalent alkyl linking group. An alkylene group formallycorresponds to an alkane with two C—H bond replaced by points ofattachment of the alkylene group to the remainder of the compound. Theterm “C_(n-m) alkylene” refers to an alkylene group having n to m carbonatoms. Examples of alkylene groups include, but are not limited to,ethan-1,2-diyl, ethan-1,1-diyl, propan-1,3-diyl, propan-1,2-diyl,propan-1,1-diyl, butan-1,4-diyl, butan-1,3-diyl, butan-1,2-diyl,2-methyl-propan-1,3-diyl and the like.

The term “alkoxy”, employed alone or in combination with other terms,refers to a group of formula —O-alkyl, wherein the alkyl group is asdefined above. The term “C_(n-m) alkoxy” refers to an alkoxy group, thealkyl group of which has n to m carbons. Example alkoxy groups includemethoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy andthe like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1to 3 carbon atoms. The term “C_(n-m) dialkoxy” refers to a linking groupof formula —O—(C_(n-m) alkyl)-O—, the alkyl group of which has n to mcarbons. Example dialkyoxy groups include —OCH₂CH₂O— and OCH₂CH₂CH₂O—.In some embodiments, the two O atoms of a C_(n-m) dialkoxy group may beattached to the same B atom to form a 5- or 6-membered heterocycloalkylgroup.

The term “amino” refers to a group of formula —NH₂.

The term “carbonyl”, employed alone or in combination with other terms,refers to a —C(═O)— group, which also may be written as C(O).

The term “cyano” or “nitrile” refers to a group of formula —C≡N, whichalso may be written as —CN.

The terms “halo” or “halogen”, used alone or in combination with otherterms, refers to fluoro, chloro, bromo and iodo. In some embodiments,“halo” refers to a halogen atom selected from F, Cl, or Br. In someembodiments, halo groups are F.

The term “haloalkyl” as used herein refers to an alkyl group in whichone or more of the hydrogen atoms has been replaced by a halogen atom.The term “C_(n-m) haloalkyl” refers to a C_(n-m) alkyl group having n tom carbon atoms and from at least one up to {2(n to m)+1} halogen atoms,which may either be the same or different. In some embodiments, thehalogen atoms are fluoro atoms. In some embodiments, the haloalkyl grouphas 1 to 6 or 1 to 4 carbon atoms. Example haloalkyl groups include CF₃,C₂F₅, CHF₂, CH₂F, CCl₃, CHCl₂, C₂Cl₅ and the like. In some embodiments,the haloalkyl group is a fluoroalkyl group.

The term “haloalkoxy”, employed alone or in combination with otherterms, refers to a group of formula —O-haloalkyl, wherein the haloalkylgroup is as defined above. The term “C_(n-m) haloalkoxy” refers to ahaloalkoxy group, the haloalkyl group of which has n to m carbons.Example haloalkoxy groups include trifluoromethoxy and the like. In someembodiments, the haloalkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

The term “oxo” refers to an oxygen atom as a divalent substituent,forming a carbonyl group when attached to carbon, or attached to aheteroatom forming a sulfoxide or sulfone group, or an N-oxide group. Insome embodiments, heterocyclic groups may be optionally substituted by 1or 2 oxo (═O) substituents.

The term “sulfido” refers to a sulfur atom as a divalent substituent,forming a thiocarbonyl group (C═S) when attached to carbon.

The term “oxidized” in reference to a ring-forming N atom refers to aring-forming N-oxide.

The term “oxidized” in reference to a ring-forming S atom refers to aring-forming sulfonyl or ring-forming sulfinyl.

The term “aromatic” refers to a carbocycle or heterocycle having one ormore polyunsaturated rings having aromatic character (i.e., having(4n+2) delocalized π (pi) electrons where n is an integer).

The term “aryl”, employed alone or in combination with other terms,refers to an aromatic hydrocarbon group, which may be monocyclic orpolycyclic (e.g., having 2 fused rings). The term “C_(n-m) aryl” refersto an aryl group having from n to m ring carbon atoms. Aryl groupsinclude, e.g., phenyl, naphthyl, and the like. In some embodiments, arylgroups have from 6 to about 10 carbon atoms. In some embodiments arylgroups have 6 carbon atoms. In some embodiments aryl groups have 10carbon atoms. In some embodiments, the aryl group is phenyl. In someembodiments, the aryl group is naphthyl.

The term “heteroaryl” or “heteroaromatic”, employed alone or incombination with other terms, refers to a monocyclic or polycyclicaromatic heterocycle having at least one heteroatom ring member selectedfrom sulfur, oxygen and nitrogen. In some embodiments, the heteroarylring has 1, 2, 3, or 4 heteroatom ring members independently selectedfrom nitrogen, sulfur and oxygen. In some embodiments, any ring-formingN in a heteroaryl moiety can be an N-oxide. In some embodiments, theheteroaryl has 5-14 ring atoms including carbon atoms and 1, 2, 3, or 4heteroatom ring members independently selected from nitrogen, sulfur andoxygen. In some embodiments, the heteroaryl has 5-10 ring atomsincluding carbon atoms and 1, 2, 3, or 4 heteroatom ring membersindependently selected from nitrogen, sulfur and oxygen. In someembodiments, the heteroaryl has 5-6 ring atoms and 1 or 2 heteroatomring members independently selected from nitrogen, sulfur and oxygen. Insome embodiments, the heteroaryl is a five-membered or six-memberedheteroaryl ring. In other embodiments, the heteroaryl is aneight-membered, nine-membered or ten-membered fused bicyclic heteroarylring. Example heteroaryl groups include, but are not limited to,pyridinyl (pyridyl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,pyrazolyl, azolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, furanyl,thiophenyl, quinolinyl, isoquinolinyl, naphthyridinyl (including 1,2-,1,3-, 1,4-, 1,5-, 1,6-, 1,7-, 1,8-, 2,3-, and 2,6-naphthyridine),indolyl, isoindolyl, benzothiophenyl, benzofuranyl, benzisoxazolyl,imidazo[1,2-b]thiazolyl, purinyl, and the like. In some embodiments, theheteroaryl group is pyridone (e.g., 2-pyridone).

A five-membered heteroaryl ring is a heteroaryl group having five ringatoms wherein one or more (e.g., 1, 2, or 3) ring atoms areindependently selected from N, O, and S. Exemplary five-membered ringheteroaryls include thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl,oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl,tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl,1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl,1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.

A six-membered heteroaryl ring is a heteroaryl group having six ringatoms wherein one or more (e.g., 1, 2, or 3) ring atoms areindependently selected from N, O, and S. Exemplary six-membered ringheteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl, isoindolyl,and pyridazinyl.

The term “cycloalkyl”, employed alone or in combination with otherterms, refers to a non-aromatic hydrocarbon ring system (monocyclic,bicyclic or polycyclic), including cyclized alkyl and alkenyl groups.The term “C_(n-m) cycloalkyl” refers to a cycloalkyl that has n to mring member carbon atoms. Cycloalkyl groups can include mono- orpolycyclic (e.g., having 2, 3, or 4 fused rings) groups and spirocycles.Cycloalkyl groups can have 3, 4, 5, 6, or 7 ring-forming carbons (C₃₋₇).In some embodiments, the cycloalkyl group has 3 to 6 ring members, 3 to5 ring members, or 3 to 4 ring members. In some embodiments, thecycloalkyl group is monocyclic. In some embodiments, the cycloalkylgroup is monocyclic or bicyclic. In some embodiments, the cycloalkylgroup is a C₃₋₆ monocyclic cycloalkyl group. Ring-forming carbon atomsof a cycloalkyl group can be optionally oxidized to form an oxo orsulfido group. Cycloalkyl groups also include cycloalkylidenes. In someembodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl. Also included in the definition of cycloalkyl are moietiesthat have one or more aromatic rings fused (i.e., having a bond incommon with) to the cycloalkyl ring, e.g., benzo or thienyl derivativesof cyclopentane, cyclohexane and the like. A cycloalkyl group containinga fused aromatic ring can be attached through any ring-forming atomincluding a ring-forming atom of the fused aromatic ring. Examples ofcycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl,cycloheptatrienyl, norbornyl, norpinyl, norcarnyl,bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, and the like. In someembodiments, the cycloalkyl group is cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl.

The term “heterocycloalkyl”, employed alone or in combination with otherterms, refers to a non-aromatic ring or ring system, which mayoptionally contain one or more alkenylene groups as part of the ringstructure, which has at least one heteroatom ring member independentlyselected from nitrogen, sulfur, oxygen and phosphorus, and which has4-10 ring members, 4-7 ring members, or 4-6 ring members. Includedwithin the term “heterocycloalkyl” are monocyclic 4-, 5-, 6-, and7-membered heterocycloalkyl groups. Heterocycloalkyl groups can includemono- or bicyclic (e.g., having two fused or bridged rings) orspirocyclic ring systems. In some embodiments, the heterocycloalkylgroup is a monocyclic group having 1, 2, or 3 heteroatoms independentlyselected from nitrogen, sulfur and oxygen. Ring-forming carbon atoms andheteroatoms of a heterocycloalkyl group can be optionally oxidized toform an oxo or sulfido group or other oxidized linkage (e.g., C(O),S(O), C(S), or S(O)₂, N-oxide etc.) or a nitrogen atom can bequaternized. The heterocycloalkyl group can be attached through aring-forming carbon atom or a ring-forming heteroatom. In someembodiments, the heterocycloalkyl group contains 0 to 3 double bonds. Insome embodiments, the heterocycloalkyl group contains 0 to 2 doublebonds. Also included in the definition of heterocycloalkyl are moietiesthat have one or more aromatic rings fused (i.e., having a bond incommon with) to the heterocycloalkyl ring, e.g., benzo or thienylderivatives of piperidine, morpholine, azepine, etc. A heterocycloalkylgroup containing a fused aromatic ring can be attached through anyring-forming atom including a ring-forming atom of the fused aromaticring. Examples of heterocycloalkyl groups include2,5-diazabicyclo[2.2.1]heptanyl; pyrrolidinyl;2,5-diazabicyclo[2.2.1]octanyl; 2,5-diazabicyclo[2.2.2]octanyl;2-oxa-5-azabicyclo[2.2.1]heptanyl (e.g.,2-oxa-5-azabicyclo[2.2.1]heptan-5-yl), morpholino;6-oxo-2,7-diazaspiro[4.4]nonanyl; azetidinyl; 2-oxopyrrolidinyl;piperidinyl; piperazinyl; and octahydro-1H-pyrrolo[2,3-c]pyridinyl.

At certain places, the definitions or embodiments refer to specificrings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwiseindicated, these rings can be attached to any ring member provided thatthe valency of the atom is not exceeded. For example, an azetidine ringmay be attached at any position of the ring, whereas an azetidin-3-ylring is attached at the 3-position.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent invention that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention. Cis and trans geometric isomers of thecompounds of the present invention are described and may be isolated asa mixture of isomers or as separated isomeric forms.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. One method includes fractionalrecrystallization using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, e.g., optically active acids,such as the D and L forms of tartaric acid, diacetyltartaric acid,dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or thevarious optically active camphorsulfonic acids such as β-camphorsulfonicacid. Other resolving agents suitable for fractional crystallizationmethods include stereoisomerically pure forms of α-methylbenzylamine(e.g., S and R forms, or diastereomerically pure forms),2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1,2-diaminocyclohexane and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

In some embodiments, the compounds of the invention have the(R)-configuration. In other embodiments, the compounds have the(S)-configuration. In compounds with more than one chiral centers, eachof the chiral centers in the compound may be independently (R) or (S),unless otherwise indicated.

Compounds of the invention also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone—enol pairs, amide—imidic acidpairs, lactam—lactim pairs, enamine−imine pairs, and annular forms wherea proton can occupy two or more positions of a heterocyclic system,e.g., 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and2H-isoindole and 1H- and 2H-pyrazole. Tautomeric forms can be inequilibrium or sterically locked into one form by appropriatesubstitution.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium. One ormore constituent atoms of the compounds of the invention can be replacedor substituted with isotopes of the atoms in natural or non-naturalabundance. In some embodiments, the compound includes at least onedeuterium atom. For example, one or more hydrogen atoms in a compound ofthe present disclosure can be replaced or substituted by deuterium. Insome embodiments, the compound includes two or more deuterium atoms. Insome embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, or 12 deuterium atoms. Synthetic methods for including isotopes intoorganic compounds are known in the art (Deuterium Labeling in OrganicChemistry by Alan F. Thomas (New York, N.Y., Appleton-Century-Crofts,1971; The Renaissance of H/D Exchange by Jens Atzrodt, Volker Derdau,Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007,7744-7765; The Organic Chemistry of Isotopic Labelling by James R.Hanson, Royal Society of Chemistry, 2011). Isotopically labeledcompounds can used in various studies such as NMR spectroscopy,metabolism experiments, and/or assays.

Substitution with heavier isotopes such as deuterium, may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample, increased in vivo half-life or reduced dosage requirements, andhence may be preferred in some circumstances. (A. Kerekes et. al. J.Med. Chem. 2011, 54, 201-210; R. Xu et. al. J. Label Compd Radiopharm.2015, 58, 308-312).

The term, “compound”, as used herein is meant to include allstereoisomers, geometric isomers, tautomers and isotopes of thestructures depicted. The term is also meant to refer to compounds of theinventions, regardless of how they are prepared, e.g., synthetically,through biological process (e.g., metabolism or enzyme conversion), or acombination thereof.

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.,hydrates and solvates) or can be isolated. When in the solid state, thecompounds described herein and salts thereof may occur in various formsand may, e.g., take the form of solvates, including hydrates. Thecompounds may be in any solid state form, such as a polymorph orsolvate, so unless clearly indicated otherwise, reference in thespecification to compounds and salts thereof should be understood asencompassing any solid state form of the compound.

In some embodiments, the compounds of the invention, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, e.g., a composition enriched in the compounds of the invention.Substantial separation can include compositions containing at leastabout 50%, at least about 60%, at least about 70%, at least about 80%,at least about 90%, at least about 95%, at least about 97%, or at leastabout 99% by weight of the compounds of the invention, or salt thereof.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The expressions, “ambient temperature” and “room temperature”, as usedherein, are understood in the art, and refer generally to a temperature,e.g., a reaction temperature, that is about the temperature of the roomin which the reaction is carried out, e.g., a temperature from about 20°C. to about 30° C.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. The term “pharmaceutically acceptablesalts” refers to derivatives of the disclosed compounds wherein theparent compound is modified by converting an existing acid or basemoiety to its salt form. Examples of pharmaceutically acceptable saltsinclude, but are not limited to, mineral or organic acid salts of basicresidues such as amines; alkali or organic salts of acidic residues suchas carboxylic acids; and the like. The pharmaceutically acceptable saltsof the present invention include the non-toxic salts of the parentcompound formed, e.g., from non-toxic inorganic or organic acids. Thepharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, alcohols (e.g., methanol, ethanol,iso-propanol or butanol) or acetonitrile (MeCN) are preferred. Lists ofsuitable salts are found in Remington's Pharmaceutical Sciences, 17^(th)Ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J.Pharm. Sci., 1977, 66(1), 1-19 and in Stahl et al., Handbook ofPharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002). Insome embodiments, the compounds described herein include the N-oxideforms.

Synthesis

Compounds of the invention, including salts thereof, can be preparedusing known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes, such as those inthe Schemes below.

The reactions for preparing compounds of the invention can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynon-reactive with the starting materials (reactants), the intermediatesor products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

Preparation of compounds of the invention can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups is described, e.g., in Kocienski, Protecting Groups,(Thieme, 2007); Robertson, Protecting Group Chemistry, (OxfordUniversity Press, 2000); Smith et al., March's Advanced OrganicChemistry: Reactions, Mechanisms, and Structure, 6^(th) Ed. (Wiley,2007); Peturssion et al., “Protecting Groups in Carbohydrate Chemistry,”J. Chem. Educ., 1997, 74(11), 1297; and Wuts et al., Protective Groupsin Organic Synthesis, 4th Ed., (Wiley, 2006).

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), massspectrometry or by chromatographic methods such as high performanceliquid chromatography (HPLC) or thin layer chromatography (TLC).

The Schemes below provide general guidance in connection with preparingthe compounds of the invention. One skilled in the art would understandthat the preparations shown in the Schemes can be modified or optimizedusing general knowledge of organic chemistry to prepare variouscompounds of the invention. Compounds of Formula (I) can be prepared,e.g., using a process as illustrated in the schemes below.

Compounds of formula 1-4 can be prepared using the process illustratedin Scheme 1. In Scheme 1, the halogen substituent in appropriatelysubstituted compounds of formula 1-1 can be converted into R¹ by anumber of methods, e.g. by nucleophilic displacement with an appropriateamine nucleophile in a suitable solvent (e.g. DMSO, DMF, dioxane) with asuitable base (e.g. triethylamine or DIPEA), or by a suitablecross-coupling, including Buchwald-Hartwig amination (Chem. Sci. 2011,2, 27-50) (e.g. in the presence of a palladium precatalyst, such asRuPhos Pd G2), Negishi (ACS Catalysis 2016, 6, 1540-1552) or Suzuki(Tetrahedron 2002, 58, 9633-9695) (e.g. in the presence of a palladiumprecatalyst, such as XPhos Pd G2), to give compounds of formula 1-2.Acylation of the aniline nitrogen with an appropriate acid halide (i.e.chloro, bromo) or acid anhydride (e.g. acetic anhydride) in a suitablesolvent (e.g. CH₂Cl₂, THF, AcOH, pyridine) provides compounds of formula1-3. Benzothiazole ring formation is accomplished via reaction with anappropriate thionating reagent (e.g. Lawesson's reagent or Na₂S) in asuitable solvent (e.g. THF, DMF) to provide compounds of formula 1-4.

Alternatively, for the later stage exploration of substitution atposition R¹, compounds of formula 2-5 can be prepared using the processdepicted in Scheme 2. In Scheme 2, appropriately substituted compoundsof formula 2-1 are converted into compounds of formula 2-2 using anappropriate acid halide (i.e. chloro, bromo) or acid anhydride (e.g.acetic anhydride) in a suitable solvent (e.g. CH₂Cl₂, THF, AcOH,pyridine). Nitration of formula 2-2 (e.g. nitric acid in the presence ofsulfuric acid) provides compounds of formula 2-3. Formation of thebenzothiazole ring is achieved via reaction with an appropriatethionating reagent (e.g. Lawesson's reagent or Na₂S) in a suitablesolvent (e.g. THF, DMF) to provide compounds of formula 2-4. Finally,the halogen substituent in the compounds of formula 2-4 can be convertedinto R¹ by a number of methods, e.g. by nucleophilic displacement withan appropriate amine nucleophile in a suitable solvent (e.g. DMSO, DMF,dioxane) with a suitable base (e.g. triethylamine or DIPEA), or by asuitable cross-coupling, including Buchwald-Hartwig amination (e.g. inthe presence of a palladium precatalyst, such as RuPhos Pd G2), Negishior Suzuki (e.g. in the presence of a palladium precatalyst, such asXPhos Pd G2), to give compounds of formula 2-5.

Compounds of formula 3-3 can be prepared using the process illustratedin Scheme 3. In Scheme 3, halogenation of an appropriately substitutedbenzothiazole of formula 3-1 is achieved via treatment with anappropriate halogenating agent (e.g. NCS, NBS) to provide compounds offormula 3-2. The halogen substituent in the compounds of formula 3-2 canthen be converted into R³ by a number of coupling methods, e.g. by asuitable cross-coupling, including Negishi or Suzuki (e.g. in thepresence of a palladium precatalyst, such as XPhos Pd G2), Pd-catalyzedcyanation (e.g. in the presence of a palladium catalyst and ligand, suchas Pd₂(dba)₃ and Xantphos, a base such as TMEDA, and an appropriatecyanating reagent, such as dicyanozinc), to give compounds of formula3-3.

Compounds of formula 4-7 with a variety of substitution at R² can beprepared using the process illustrated in Scheme 4. In Scheme 4, anappropriately substituted aniline of formula 4-1 is converted into aformamide via treatment with formic acid in the presence of aceticanhydride to provide compounds of formula 4-2. Nitration of formula 4-2(e.g. nitric acid in the presence of sulfuric acid) provides compoundsof formula 4-3. Benzothiazole ring formation is accomplished viareaction with an appropriate thionating reagent (e.g. Na₂S) in asuitable solvent (e.g. DMF) to provide compounds of formula 4-4. Thehalogen substituent in appropriately substituted compounds of formula4-4 can be converted into R¹ by a number of methods, e.g. bynucleophilic displacement with the appropriate amine nucleophile in asuitable solvent (e.g. DMSO, DMF, dioxane) with a suitable base (e.g.triethylamine or DIPEA) to give compounds of formula 4-5. Halogenationof appropriately substituted compounds of formula 4-5 via treatment witha base (e.g. LDA) in a suitable solvent (e.g. THF) and a halogenatingagent (e.g. carbon tetrabromide) provides compounds of formula 4-6.Finally, the halogen substituent in appropriately substituted compoundsof formula 4-6 can be converted into R² by a suitable cross-coupling,e.g. Negishi or Suzuki (e.g. in the presence of a palladium precatalyst,such as RuPhos Pd G2), or Stille (ACS Catalysis 2015, 5, 3040-3053)(e.g. in the presence of a palladium catalyst such as (PPh₃)₂PdCl₂ andbase such as triethylamine) to give compounds of formula 4-7.

Compounds of formula I can be prepared using the process illustrated inScheme 5. In the process depicted in Scheme 5, reduction of the nitrogroup in appropriately substituted compounds of formula 5-1 with anappropriate reducing agent (e.g. iron in the presence of ammoniumchloride) affords compounds of formula 5-2. Finally, compounds of thedesired formula I are accessed by amide bond formation that is achievedvia the union of compounds of formula 5-2 with acids of formula 5-4(e.g. using HATU and a base such as triethylamine in an appropriatesolvent such as DMF). The required acids of formula 5-4 can be preparedby coupling of a heteroaryl halide (i.e. chloro, bromo or iodo) offormula 5-3 and Cy^(B)-M (M=e.g. appropriately functionalized boron,stannyl or zinc species) by a suitable cross-cross coupling, such asSuzuki (e.g. in the presence of a palladium precatalyst, such as XPhosPd G2, and a base such as potassium phosphate, tribasic) or Stille (e.g.in the presence of a palladium catalyst such as (PPh₃)₂PdCl₂ and basesuch as triethylamine).

HPK1 Kinase

Studies have established that HPK1 is a negative regulator of T cell andB cell activation (Hu, M. C., et al., Genes Dev, 1996. 10(18): p.2251-64; Kiefer, F., et al., EMBO J, 1996. 15(24): p. 7013-25).HPK1-deficient mouse T cells showed dramatically increased activation ofTCR proximal signaling, enhanced IL-2 production, andhyper-proliferation in vitro upon anti-CD3 stimulation (Shui, J. W., etal., Nat Immunol, 2007. 8(1): p. 84-91). Similar to T cells, HPK1knockout B cells produced much higher levels of IgM and IgG isoformsafter KLH immunization and displayed hyper-proliferation potentially asa result of enhanced BCR signaling. Wang, X., et al., J Biol Chem, 2012.287(14): p. 11037-48. Mechanistically, during TCR or BCR signaling, HPK1is activated by LCK/ZAP70 (T cells) or SYK/LYN (B cells) mediated-Tyr379phosphorylation and its subsequent binding to adaptor protein SLP-76 (Tcells) or BLNK (B cells) (Wang, X., et al., J Biol Chem, 2012. 287(14):p. 11037-48). Activated HPK1 phosphorylates SLP-76 on Ser376 or BLNK onThr152, leading to the recruitment of signaling molecule 14-3-3 andultimate ubiquitination-mediated degradation of SLP-76 or BLNK (Liou,J., et al., Immunity, 2000. 12(4): p. 399-408; Di Bartolo, V., et al., JExp Med, 2007. 204(3): p. 681-91). As SLP-76 and BLNK are essential forTCR/BCR-mediated signaling activation (e.g. ERK, phospholipase Cγ1,calcium flux, and NFAT activation), HPK1-mediated downregulation ofthese adaptor proteins provide a negative feedback mechanism toattenuate signaling intensity during T cell or B cell activation (Wang,X., et al., J Biol Chem, 2012. 287(14): p. 11037-48).

The bone marrow-derived dendritic cells (BDMCs) from HPK1 knockout miceshowed higher expression of co-stimulatory molecules (e.g. CD80/CD86)and enhanced production of proinflammatory cytokines (IL-12, TNF-α etc),and demonstrated superior ability to stimulate T cell proliferation invitro and in vivo as compared to wild-type DCs (Alzabin, S., et al., JImmunol, 2009. 182(10): p. 6187-94). These data suggest that HPK1 isalso an important negative regulator of dendritic cell activation(Alzabin, S., et al., J Immunol, 2009. 182(10): p. 6187-94). However,the signaling mechanisms underlying HPK-1 mediated negative regulationof DC activation remains to be elucidated.

In contrast, HPK1 appears to be a positive regulator of suppressivefunctions of regulatory T cells (Treg) (Sawasdikosol, S. et al., Thejournal of immunology, 2012. 188(supplement 1): p. 163). HPK1 deficientmouse Foxp3+ Tregs were defective in suppressing TCR-induced effector Tcell proliferation, and paradoxically gained the ability to produce IL-2following TCR engagement (Sawasdikosol, S. et al., The Journal ofImmunology, 2012. 188(supplement 1): p. 163). These data suggest thatHPK1 is an important regulator of Treg functions and peripheralself-tolerance.

HPK1 was also involved in PGE2-mediated inhibition of CD4+ T cellactivation (Ikegami, R., et al., J Immunol, 2001. 166(7): p. 4689-96).Studies published in US 2007/0087988 indicated that HPK1 kinase activitywas increased by exposure to physiological concentrations of PGE2 inCD4+ T cells and this effect was mediated by PEG2-induced PKAactivation. The proliferation of HPK1 deficient T cells was resistant tothe suppressive effects of PGE2 (see US 2007/0087988). Therefore,PGE2-mediated activation of HPK1 may represent a novel regulatorypathway of modulating immune response.

The present disclosure provides methods of modulating (e.g., inhibiting)HPK1 activity, by contacting HPK1 with a compound of the invention, or apharmaceutically acceptable salt thereof. In some embodiments, thecontacting can be administering to a patient a compound provided herein,or a pharmaceutically acceptable salt thereof. In certain embodiments,the compounds of the present disclosure, or pharmaceutically acceptablesalts thereof, are useful for therapeutic administration to enhance,stimulate and/or increase immunity in cancer. For example, a method oftreating a disease or disorder associated with inhibition of HPK1interaction can include administering to a patient in need thereof atherapeutically effective amount of a compound provided herein, or apharmaceutically acceptable salt thereof. The compounds of the presentdisclosure can be used alone, in combination with other agents ortherapies or as an adjuvant or neoadjuvant for the treatment of diseasesor disorders, including cancers. For the uses described herein, any ofthe compounds of the disclosure, including any of the embodimentsthereof, may be used.

Examples of cancers that are treatable using the compounds of thepresent disclosure include, but are not limited to, bone cancer,pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous orintraocular malignant melanoma, uterine cancer, ovarian cancer, rectalcancer, cancer of the anal region, stomach cancer, testicular cancer,uterine cancer, carcinoma of the fallopian tubes, carcinoma of theendometrium, endometrial cancer, carcinoma of the cervix, carcinoma ofthe vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin'slymphoma, cancer of the esophagus, cancer of the small intestine, cancerof the endocrine system, cancer of the thyroid gland, cancer of theparathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue,cancer of the urethra, cancer of the penis, chronic or acute leukemiasincluding acute myeloid leukemia, chronic myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors ofchildhood, lymphocytic lymphoma, cancer of the bladder, cancer of thekidney or urethra, carcinoma of the renal pelvis, neoplasm of thecentral nervous system (CNS), primary CNS lymphoma, tumor angiogenesis,spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi'ssarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma,environmentally induced cancers including those induced by asbestos, andcombinations of said cancers.

In some embodiments, cancers treatable with compounds of the presentdisclosure include melanoma (e.g., metastatic malignant melanoma), renalcancer (e.g. clear cell carcinoma), prostate cancer (e.g. hormonerefractory prostate adenocarcinoma), breast cancer, triple-negativebreast cancer, colon cancer and lung cancer (e.g. non-small cell lungcancer and small cell lung cancer). Additionally, the disclosureincludes refractory or recurrent malignancies whose growth may beinhibited using the compounds of the disclosure.

In some embodiments, cancers that are treatable using the compounds ofthe present disclosure include, but are not limited to, solid tumors(e.g., prostate cancer, colon cancer, esophageal cancer, endometrialcancer, ovarian cancer, uterine cancer, renal cancer, hepatic cancer,pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancersof the head and neck, thyroid cancer, glioblastoma, sarcoma, bladdercancer, etc.), hematological cancers (e.g., lymphoma, leukemia such asacute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML),chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML),DLBCL, mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed orrefractory NHL and recurrent follicular), Hodgkin lymphoma or multiplemyeloma) and combinations of said cancers. In some embodiments, diseasesand indications that are treatable using the compounds of the presentdisclosure include, but are not limited to hematological cancers,sarcomas, lung cancers, gastrointestinal cancers, genitourinary tractcancers, liver cancers, bone cancers, nervous system cancers,gynecological cancers, and skin cancers.

Exemplary hematological cancers include lymphomas and leukemias such asacute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML),acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL),chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma(DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsedor refractory NHL and recurrent follicular), Hodgkin lymphoma,myeloproliferative diseases (e.g., primary myelofibrosis (PMF),polycythemia vera (PV), essential thrombocytosis (ET)), myelodysplasiasyndrome (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), multiplemyeloma, cutaneous T-cell lymphoma, Waldenstrom's Macroglubulinemia,hairy cell lymphoma, chronic myelogenic lymphoma and Burkitt's lymphoma.

Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma,osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma,myxoma, rhabdomyoma, rhabdosarcoma, fibroma, lipoma, harmatoma, andteratoma.

Exemplary lung cancers include non-small cell lung cancer (NSCLC), smallcell lung cancer, bronchogenic carcinoma (squamous cell,undifferentiated small cell, undifferentiated large cell,adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma,chondromatous hamartoma, and mesothelioma.

Exemplary gastrointestinal cancers include cancers of the esophagus(squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma),stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductaladenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors,vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors,Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma),large bowel (adenocarcinoma, tubular adenoma, villous adenoma,hamartoma, leiomyoma), and colorectal cancer.

Exemplary genitourinary tract cancers include cancers of the kidney(adenocarcinoma, Wilm's tumor [nephroblastoma]), bladder and urethra(squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma),prostate (adenocarcinoma, sarcoma), and testis (seminoma, teratoma,embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma,interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors,lipoma).

Exemplary liver cancers include hepatoma (hepatocellular carcinoma),cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellularadenoma, and hemangioma.

Exemplary bone cancers include, for example, osteogenic sarcoma(osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochronfroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant celltumors Exemplary nervous system cancers include cancers of the skull(osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges(meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma,meduoblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma,glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma,congenital tumors), and spinal cord (neurofibroma, meningioma, glioma,sarcoma), as well as neuroblastoma and Lhermitte-Duclos disease.

Exemplary gynecological cancers include cancers of the uterus(endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervicaldysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma,mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecalcell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignantteratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma,adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma,squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma),and fallopian tubes (carcinoma).

Exemplary skin cancers include melanoma, basal cell carcinoma, squamouscell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer, molesdysplastic nevi, lipoma, angioma, dermatofibroma, and keloids. In someembodiments, diseases and indications that are treatable using thecompounds of the present disclosure include, but are not limited to,sickle cell disease (e.g., sickle cell anemia), triple-negative breastcancer (TNBC), myelodysplastic syndromes, testicular cancer, bile ductcancer, esophageal cancer, and urothelial carcinoma.

Exemplary head and neck cancers include glioblastoma, melanoma,rhabdosarcoma, lymphosarcoma, osteosarcoma, squamous cell carcinomas,adenocarcinomas, oral cancer, laryngeal cancer, nasopharyngeal cancer,nasal and paranasal cancers, thyroid and parathyroid cancers.

In some embodiments, cancers that are treatable using the compounds ofthe present disclosure include breast cancer, colorectal cancer, lungcancer, ovarian cancer, and pancreatic cancer.

In some embodiments, HPK1 inhibitors may be used to treat tumorsproducing PGE2 (e.g. Cox-2 overexpressing tumors) and/or adenosine (CD73and CD39 over-expressing tumors). Overexpression of Cox-2 has beendetected in a number of tumors, such as colorectal, breast, pancreaticand lung cancers, where it correlates with a poor prognosis.Overexpression of COX-2 has been reported in hematological cancer modelssuch as RAJI (Burkitt's lymphoma) and U937 (acute promonocytic leukemia)as well as in patient's blast cells. CD73 is up-regulated in varioushuman carcinomas including those of colon, lung, pancreas and ovary.Importantly, higher expression levels of CD73 are associated with tumorneovascularization, invasiveness, and metastasis and with shorterpatient survival time in breast cancer.

As used herein, the term “contacting” refers to the bringing together ofthe indicated moieties in an in vitro system or an in vivo system suchthat they are in sufficient physical proximity to interact.

The terms “individual” or “patient”, used interchangeably, refer to anyanimal, including mammals, preferably mice, rats, other rodents,rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and mostpreferably humans.

The phrase “therapeutically effective amount” refers to the amount ofactive compound or pharmaceutical agent that elicits the biological ormedicinal response in a tissue, system, animal, individual or human thatis being sought by a researcher, veterinarian, medical doctor or otherclinician.

As used herein, the term “treating” or “treatment” refers to one or moreof (1) inhibiting the disease; e.g., inhibiting a disease, condition ordisorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology);and (2) ameliorating the disease; e.g., ameliorating a disease,condition or disorder in an individual who is experiencing or displayingthe pathology or symptomatology of the disease, condition or disorder(i.e., reversing the pathology and/or symptomatology) such as decreasingthe severity of disease.

In some embodiments, the compounds of the invention are useful inpreventing or reducing the risk of developing any of the diseasesreferred to herein; e.g., preventing or reducing the risk of developinga disease, condition or disorder in an individual who may be predisposedto the disease, condition or disorder but does not yet experience ordisplay the pathology or symptomatology of the disease.

Combination Therapies

I. Immune-Checkpoint Therapies

In some embodiments, the HPK1 inhibitors provided herein can be used incombination with one or more immune checkpoint inhibitors for thetreatment of cancer as described herein. Compounds of the presentdisclosure can be used in combination with one or more immune checkpointinhibitors. Exemplary immune checkpoint inhibitors include inhibitorsagainst immune checkpoint molecules such as CD20, CD28, CD40, CD122,CD96, CD73, CD47, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM,arginase, HPK1, CD137 (also known as 4-1B), ICOS, B7-H3, B7-H4, BTLA,CTLA-4, LAG3, TIM3, VISTA, TIGIT, PD-1, PD-L1 and PD-L2. In someembodiments, the immune checkpoint molecule is a stimulatory checkpointmolecule selected from CD27, CD28, CD40, ICOS, OX40, GITR and CD137. Insome embodiments, the immune checkpoint molecule is an inhibitorycheckpoint molecule selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO,KIR, LAG3, PD-1, TIM3, TIGIT, and VISTA. In some embodiments, thecompounds of the disclosure provided herein can be used in combinationwith one or more agents selected from KIR inhibitors, TIGIT inhibitors,LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFR betainhibitors.

In some embodiments, the HPK1 inhibitors provided herein can be used incombination with one or more agonists of immune checkpoint molecules,e.g., OX40, CD27, OX40, GITR, and CD137 (also known as 4-1B).

In some embodiments, the inhibitor of an immune checkpoint molecule isanti-PD1 antibody, anti-PD-L1 antibody, or anti-CTLA-4 antibody.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In someembodiments, the anti-PD-1 monoclonal antibody is nivolumab,pembrolizumab (also known as MK-3475), durvalumab (Imfinzi®),pidilizumab, SHR-1210, PDR001, MGA012, PDR001, AB122, or AMP-224. Insome embodiments, the anti-PD-1 monoclonal antibody is nivolumab orpembrolizumab. In some embodiments, the anti-PD1 antibody ispembrolizumab. In some embodiments, the anti-PD-1 monoclonal antibody isMGA012. In some embodiments, the anti-PD1 antibody is SHR-1210. Otheranti-cancer agent(s) include antibody therapeutics such as 4-1BB (e.g.urelumab, utomilumab.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In someembodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736,MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments,the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1 and PD-L1, e.g., an anti-PD-1/PD-L1 monoclonalantibody. In some embodiments, the anti-PD-1/PD-L1 is MCLA-136.

In some embodiments, the compounds of the disclosure can be used incombination with INCB086550.

In some embodiments, the inhibitor is MCLA-145.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In someembodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab,AGEN1884, or CP-675, 206.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments,the anti-LAG3 antibody is BMS-986016, LAG525, or INCAGN2385.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of TIM3, e.g., an anti-TIM3 antibody. In some embodiments,the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments,the anti-GITR antibody is TRX518, MK-4166, INCAGN1876, MK-1248, AMG228,BMS-986156, GWN323, or MEDI1873.

In some embodiments, the inhibitor of an immune checkpoint molecule isan agonist of OX40, e.g., OX40 agonist antibody or OX40L fusion protein.In some embodiments, the anti-OX40 antibody is MEDI0562, MOXR-0916,PF-04518600, GSK3174998, or BMS-986178. In some embodiments, the OX40Lfusion protein is MEDI6383.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD20, e.g., an anti-CD20 antibody. In some embodiments,the anti-CD20 antibody is obinutuzumab or rituximab.

The compounds of the present disclosure can be used in combination withbispecific antibodies. In some embodiments, one of the domains of thebispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3,CD137, ICOS, CD3 or TGFβ receptor.

In some embodiments, the compounds of the disclosure can be used incombination with one or more metabolic enzyme inhibitors. In someembodiments, the metabolic enzyme inhibitor is an inhibitor of IDO1,TDO, or arginase. Examples of IDO1 inhibitors include epacadostat,NLG919, BMS-986205, PF-06840003, IOM2983, RG-70099 and LY338196.

As provided throughout, the additional compounds, inhibitors, agents,etc. can be combined with the present compound in a single or continuousdosage form, or they can be administered simultaneously or sequentiallyas separate dosage forms.

II. Cancer Therapies

Cancer cell growth and survival can be impacted by multiple signalingpathways. Thus, it is useful to combine differentenzyme/protein/receptor inhibitors, exhibiting different preferences inthe targets which they modulate the activities of, to treat suchconditions. Examples of agents that may be combined with compounds ofthe present disclosure include inhibitors of the PI3K-AKT-mTOR pathway,inhibitors of the Raf-MAPK pathway, inhibitors of JAK-STAT pathway,inhibitors of beta catenin pathway, inhibitors of notch pathway,inhibitors of hedgehog pathway, inhibitors of Pim kinases, andinhibitors of protein chaperones and cell cycle progression. Targetingmore than one signaling pathway (or more than one biological moleculeinvolved in a given signaling pathway) may reduce the likelihood ofdrug-resistance arising in a cell population, and/or reduce the toxicityof treatment.

The compounds of the present disclosure can be used in combination withone or more other enzyme/protein/receptor inhibitors for the treatmentof diseases, such as cancer. Examples of cancers include solid tumorsand liquid tumors, such as blood cancers. For example, the compounds ofthe present disclosure can be combined with one or more inhibitors ofthe following kinases for the treatment of cancer: Akt1, Akt2, Akt3,TGF-DR, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK,MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFαR, PDGFβR,CSFIR, KIT, FLK-II, KDR/FLK-1, FLK-4, fit-1, FGFR1, FGFR2, FGFR3, FGFR4,c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR/Flt2, Flt4, EphA1, EphA2,EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK,ABL, ALK and B-Raf. In some embodiments, the compounds of the presentdisclosure can be combined with one or more of the following inhibitorsfor the treatment of cancer. Non-limiting examples of inhibitors thatcan be combined with the compounds of the present disclosure fortreatment of cancers include an FGFR inhibitor (FGFR1, FGFR2, FGFR3 orFGFR4, e.g., AZD4547, BAY1187982, ARQ087, BGJ398, BIBF1120, TKI258,lucitanib, dovitinib, TAS-120, JNJ-42756493, Debiol347, INCB54828,INCB62079 and INCB63904), a JAK inhibitor (JAK1 and/or JAK2, e.g.,ruxolitinib, baricitinib or INCB39110), an IDO inhibitor (e.g.,epacadostat and NLG919), an LSD1 inhibitor (e.g., GSK2979552, INCB59872and INCB60003), a TDO inhibitor, a PI3K-delta inhibitor (e.g., INCB50797and INCB50465), a PI3K-gamma inhibitor such as a PI3K-gamma selectiveinhibitor, a CSF1R inhibitor (e.g., PLX3397 and LY3022855), a TAMreceptor tyrosine kinases (Tyro-3, Axl, and Mer), an angiogenesisinhibitor, an interleukin receptor inhibitor, bromo and extra terminalfamily members inhibitors (for example, bromodomain inhibitors or BETinhibitors such as OTX015, CPI-0610, INCB54329 and INCB57643) and anadenosine receptor antagonist or combinations thereof. Inhibitors ofHDAC such as panobinostat and vorinostat. Inhibitors of c-Met such asonartumzumab, tivantnib, and INC-280. Inhibitors of BTK such asibrutinib. Inhibitors of mTOR such as rapamycin, sirolimus,temsirolimus, and everolimus. Inhibitors of Raf, such as vemurafenib anddabrafenib. Inhibitors of MEK such as trametinib, selumetinib andGDC-0973. Inhibitors of Hsp90 (e.g., tanespimycin), cyclin dependentkinases (e.g., palbociclib), PARP (e.g., olaparib) and Pim kinases(LGH447, INCB053914 and SGI-1776) can also be combined with compounds ofthe present disclosure.

Compounds of the present disclosure can be used in combination with oneor more agents for the treatment of diseases such as cancer. In someembodiments, the agent is an alkylating agent, a proteasome inhibitor, acorticosteroid, or an immunomodulatory agent. Examples of an alkylatingagent include bendamustine, nitrogen mustards, ethylenimine derivatives,alkyl sulfonates, nitrosoureas and triazenes, uracil mustard,chlormethine, cyclophosphamide (Cytoxan™), ifosfamide, melphalan,chlorambucil, pipobroman, triethylene-melamine,triethylenethiophosphoramine, busulfan, carmustine, lomustine,streptozocin, dacarbazine, and temozolomide. In some embodiments, theproteasome inhibitor is carfilzomib. In some embodiments, thecorticosteroid is dexamethasone (DEX). In some embodiments, theimmunomodulatory agent is lenalidomide (LEN) or pomalidomide (POM).

The compounds of the present disclosure can further be used incombination with other methods of treating cancers, for example bychemotherapy, irradiation therapy, tumor-targeted therapy, adjuvanttherapy, immunotherapy or surgery. Examples of immunotherapy includecytokine treatment (e.g., interferons, GM-CSF, G-CSF, IL-2), CRS-207immunotherapy, cancer vaccine, monoclonal antibody, adoptive T celltransfer, CAR (Chimeric antigen receptor) T cell treatment as a boosterfor T cell activation, oncolytic virotherapy and immunomodulating smallmolecules, including thalidomide or JAK1/2 inhibitor and the like. Thecompounds can be administered in combination with one or moreanti-cancer drugs, such as a chemotherapeutics. Examplechemotherapeutics include any of abarelix, abiraterone, afatinib,aflibercept, aldesleukin, alemtuzumab, alitretinoin, allopurinol,altretamine, amsacrine, anastrozole, aphidicolon, arsenic trioxide,asparaginase, axitinib, azacitidine, bevacizumab, bexarotene,baricitinib, bicalutamide, bleomycin, bortezombi, bortezomib, brivanib,buparlisib, busulfan intravenous, busulfan oral, calusterone, camptosar,capecitabine, carboplatin, carmustine, cediranib, cetuximab,chlorambucil, cisplatin, cladribine, clofarabine, crizotinib,cyclophosphamide, cytarabine, dacarbazine, dacomitinib, dactinomycin,dalteparin sodium, dasatinib, dactinomycin, daunorubicin, decitabine,degarelix, denileukin, denileukin diftitox, deoxycoformycin,dexrazoxane, docetaxel, doxorubicin, droloxafine, dromostanolonepropionate, eculizumab, enzalutamide, epidophyllotoxin, epirubicin,epothilones, erlotinib, estramustine, etoposide phosphate, etoposide,exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine,fluorouracil, flutamide, fulvestrant, gefitinib, gemcitabine, gemtuzumabozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan,idarubicin, idelalisib, ifosfamide, imatinib mesylate, interferon alfa2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole,leucovorin, leuprolide acetate, levamisole, lomustine, meclorethamine,megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen,mithramycin, mitomycin C, mitotane, mitoxantrone, nandrolonephenpropionate, navelbene, necitumumab, nelarabine, neratinib,nilotinib, nilutamide, nofetumomab, oserelin, oxaliplatin, paclitaxel,pamidronate, panitumumab, pazopanib, pegaspargase, pegfilgrastim,pemetrexed disodium, pentostatin, pilaralisib, pipobroman, plicamycin,ponatinib, porfimer, prednisone, procarbazine, quinacrine, ranibizumab,rasburicase, regorafenib, reloxafine, revlimid, rituximab, ruxolitinib,sorafenib, streptozocin, sunitinib, sunitinib maleate, tamoxifen,tegafur, temozolomide, teniposide, testolactone, thalidomide,thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab,tretinoin, triptorelin, uracil mustard, valrubicin, vandetanib,vinblastine, vincristine, vindesine, vinorelbine, vorinostat, andzoledronate.

Other anti-cancer agent(s) include antibody therapeutics such astrastuzumab (Herceptin), antibodies to costimulatory molecules such asCTLA-4 (e.g., ipilimumab or tremelimumab), 4-1BB, antibodies to PD-1 andPD-L1, or antibodies to cytokines (IL-10, TGF-β, etc.). Examples ofantibodies to PD-1 and/or PD-L1 that can be combined with compounds ofthe present disclosure for the treatment of cancer or infections such asviral, bacteria, fungus and parasite infections include, but are notlimited to, nivolumab, pembrolizumab, MPDL3280A, MEDI-4736 and SHR-1210.

Other anti-cancer agents include inhibitors of kinases associated cellproliferative disorder. These kinases include but not limited toAurora-A, CDK1, CDK2, CDK3, CDK5, CDK7, CDK8, CDK9, ephrin receptorkinases, CHK1, CHK2, SRC, Yes, Fyn, Lck, Fer, Fes, Syk, Itk, Bmx, GSK3,JNK, PAK1, PAK2, PAK3, PAK4, PDK1, PKA, PKC, Rsk, and SGK.

Other anti-cancer agents also include those that block immune cellmigration such as antagonists to chemokine receptors, including CCR2 andCCR4.

The compounds of the present disclosure can further be used incombination with one or more anti-inflammatory agents, steroids,immunosuppressants or therapeutic antibodies. The steroids include butare not limited to 17 alpha-ethinylestradiol, diethylstilbestrol,testosterone, prednisone, fluoxymesterone, methylprednisolone,methyltestosterone, prednisolone, triamcinolone, chlorotrianisene,hydroxyprogesterone, aminoglutethimide, and medroxyprogesteroneacetate.

The compounds of the present disclosure can also be used in combinationwith lonafarnib (SCH6636), tipifarnib (R¹¹⁵⁷⁷⁷), L778123, BMS 214662,tezacitabine (MDL 101731), Sml1, triapine, didox, trimidox, and amidox.

The compounds of Formula (I) or any of the formulas as described herein,a compound as recited in any of the claims and described herein, orsalts thereof can be combined with another immunogenic agent, such ascancerous cells, purified tumor antigens (including recombinantproteins, peptides, and carbohydrate molecules), cells, and cellstransfected with genes encoding immune stimulating cytokines.Non-limiting examples of tumor vaccines that can be used includepeptides of melanoma antigens, such as peptides of gp100, MAGE antigens,Trp-2, MARTI and/or tyrosinase, or tumor cells transfected to expressthe cytokine GM-CSF.

The compounds of Formula (I) or any of the formulas as described herein,a compound as recited in any of the claims and described herein, orsalts thereof can be used in combination with a vaccination protocol forthe treatment of cancer. In some embodiments, the tumor cells aretransduced to express GM-CSF. In some embodiments, tumor vaccinesinclude the proteins from viruses implicated in human cancers such asHuman Papilloma Viruses (HPV), Hepatitis Viruses (HBV and HCV), andKaposi's Herpes Sarcoma Virus (KHSV). In some embodiments, the compoundsof the present disclosure can be used in combination with tumor specificantigen such as heat shock proteins isolated from tumor tissue itself.In some embodiments, the compounds of Formula (I) or any of the formulasas described herein, a compound as recited in any of the claims anddescribed herein, or salts thereof can be combined with dendritic cellsimmunization to activate potent anti-tumor responses.

The compounds of the present disclosure can be used in combination withbispecific macrocyclic peptides that target Fe alpha or Fe gammareceptor-expressing effectors cells to tumor cells. The compounds of thepresent disclosure can also be combined with macrocyclic peptides thatactivate host immune responsiveness.

The compounds of the present disclosure can be used in combination withbone marrow transplant for the treatment of a variety of tumors ofhematopoietic origin.

Suitable antiviral agents contemplated for use in combination with thecompounds of the present disclosure can comprise nucleoside andnucleotide reverse transcriptase inhibitors (NRTIs), non-nucleosidereverse transcriptase inhibitors (NNRTIs), protease inhibitors and otherantiviral drugs.

Example suitable NRTIs include zidovudine (AZT); didanosine (ddl);zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir(1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194);BCH-10652; emitricitabine [(−)-FTC]; beta-L-FD4 (also called beta-L-D4Cand named beta-L-2′, 3′-dicleoxy-5-fluoro-cytidene); DAPD,((−)-beta-D-2,6-diamino-purine dioxolane); and lodenosine (FddA).Typical suitable NNRTIs include nevirapine (BI-RG-587); delaviradine(BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442(1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione);and (+)-calanolide A (NSC-675451) and B. Typical suitable proteaseinhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538);indinavir (MK-639); nelfnavir (AG-1343); amprenavir (141W94); lasinavir(BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1 549. Otherantiviral agents include hydroxyurea, ribavirin, IL-2, IL-12,pentafuside and Yissum Project No. 11607.

When more than one pharmaceutical agent is administered to a patient,they can be administered simultaneously, separately, sequentially, or incombination (e.g., for more than two agents).

Formulation, Dosage Forms and Administration

When employed as pharmaceuticals, the compounds of the presentdisclosure can be administered in the form of pharmaceuticalcompositions. Thus the present disclosure provides a compositioncomprising a compound of Formula (I) or any of the formulas as describedherein, a compound as recited in any of the claims and described herein,or a pharmaceutically acceptable salt thereof, or any of the embodimentsthereof, and at least one pharmaceutically acceptable carrier orexcipient. These compositions can be prepared in a manner well known inthe pharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is indicated and uponthe area to be treated. Administration may be topical (includingtransdermal, epidermal, ophthalmic and to mucous membranes includingintranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalationor insufflation of powders or aerosols, including by nebulizer;intratracheal or intranasal), oral or parenteral. Parenteraladministration includes intravenous, intraarterial, subcutaneous,intraperitoneal intramuscular or injection or infusion; or intracranial,e.g., intrathecal or intraventricular, administration. Parenteraladministration can be in the form of a single bolus dose, or may be,e.g., by a continuous perfusion pump. Pharmaceutical compositions andformulations for topical administration may include transdermal patches,ointments, lotions, creams, gels, drops, suppositories, sprays, liquidsand powders. Conventional pharmaceutical carriers, aqueous, powder oroily bases, thickeners and the like may be necessary or desirable.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, the compound of the present disclosure or apharmaceutically acceptable salt thereof, in combination with one ormore pharmaceutically acceptable carriers or excipients. In someembodiments, the composition is suitable for topical administration. Inmaking the compositions of the invention, the active ingredient istypically mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier in the form of, e.g., a capsule, sachet, paper, orother container. When the excipient serves as a diluent, it can be asolid, semi-solid, or liquid material, which acts as a vehicle, carrieror medium for the active ingredient. Thus, the compositions can be inthe form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, e.g., up to 10% by weightof the active compound, soft and hard gelatin capsules, suppositories,sterile injectable solutions and sterile packaged powders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g., about 40 mesh.

The compounds of the invention may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the invention can beprepared by processes known in the art see, e.g., WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

In some embodiments, the pharmaceutical composition comprises silicifiedmicrocrystalline cellulose (SMCC) and at least one compound describedherein, or a pharmaceutically acceptable salt thereof. In someembodiments, the silicified microcrystalline cellulose comprises about98% microcrystalline cellulose and about 2% silicon dioxide w/w.

In some embodiments, the composition is a sustained release compositioncomprising at least one compound described herein, or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier or excipient. In some embodiments, the composition comprises atleast one compound described herein, or a pharmaceutically acceptablesalt thereof, and at least one component selected from microcrystallinecellulose, lactose monohydrate, hydroxypropyl methylcellulose andpolyethylene oxide. In some embodiments, the composition comprises atleast one compound described herein, or a pharmaceutically acceptablesalt thereof, and microcrystalline cellulose, lactose monohydrate andhydroxypropyl methylcellulose. In some embodiments, the compositioncomprises at least one compound described herein, or a pharmaceuticallyacceptable salt thereof, and microcrystalline cellulose, lactosemonohydrate and polyethylene oxide. In some embodiments, the compositionfurther comprises magnesium stearate or silicon dioxide. In someembodiments, the microcrystalline cellulose is Avicel PH102™. In someembodiments, the lactose monohydrate is Fast-flo 316™. In someembodiments, the hydroxypropyl methylcellulose is hydroxypropylmethylcellulose 2208 K4M (e.g., Methocel K4 M Premier™) and/orhydroxypropyl methylcellulose 2208 K100LV (e.g., Methocel KOOLV™). Insome embodiments, the polyethylene oxide is polyethylene oxide WSR 1105(e.g., Polyox WSR 1105™)

In some embodiments, a wet granulation process is used to produce thecomposition. In some embodiments, a dry granulation process is used toproduce the composition.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 1,000 mg (1 g), more usually about 100mg to about 500 mg, of the active ingredient. In some embodiments, eachdosage contains about 10 mg of the active ingredient. In someembodiments, each dosage contains about 50 mg of the active ingredient.In some embodiments, each dosage contains about 25 mg of the activeingredient. The term “unit dosage forms” refers to physically discreteunits suitable as unitary dosages for human subjects and other mammals,each unit containing a predetermined quantity of active materialcalculated to produce the desired therapeutic effect, in associationwith a suitable pharmaceutical excipient.

The components used to formulate the pharmaceutical compositions are ofhigh purity and are substantially free of potentially harmfulcontaminants (e.g., at least National Food grade, generally at leastanalytical grade, and more typically at least pharmaceutical grade).Particularly for human consumption, the composition is preferablymanufactured or formulated under Good Manufacturing Practice standardsas defined in the applicable regulations of the U.S. Food and DrugAdministration. For example, suitable formulations may be sterile and/orsubstantially isotonic and/or in full compliance with all GoodManufacturing Practice regulations of the U.S. Food and DrugAdministration.

The active compound may be effective over a wide dosage range and isgenerally administered in a therapeutically effective amount. It will beunderstood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms and the like.

The therapeutic dosage of a compound of the present invention can varyaccording to, e.g., the particular use for which the treatment is made,the manner of administration of the compound, the health and conditionof the patient, and the judgment of the prescribing physician. Theproportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, e.g., about 0.1 to about 1000 mg of the activeingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions can be nebulized by use of inert gases. Nebulized solutionsmay be breathed directly from the nebulizing device or the nebulizingdevice can be attached to a face mask, tent, or intermittent positivepressure breathing machine. Solution, suspension, or powder compositionscan be administered orally or nasally from devices which deliver theformulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. Insome embodiments, ointments can contain water and one or morehydrophobic carriers selected from, e.g., liquid paraffin,polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and thelike. Carrier compositions of creams can be based on water incombination with glycerol and one or more other components, e.g.,glycerinemonostearate, PEG-glycerinemonostearate and cetylstearylalcohol. Gels can be formulated using isopropyl alcohol and water,suitably in combination with other components such as, e.g., glycerol,hydroxyethyl cellulose, and the like. In some embodiments, topicalformulations contain at least about 0.1, at least about 0.25, at leastabout 0.5, at least about 1, at least about 2 or at least about 5 wt %of the compound of the invention. The topical formulations can besuitably packaged in tubes of, e.g., 100 g which are optionallyassociated with instructions for the treatment of the select indication,e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers or stabilizers will resultin the formation of pharmaceutical salts.

The therapeutic dosage of a compound of the present invention can varyaccording to, e.g., the particular use for which the treatment is made,the manner of administration of the compound, the health and conditionof the patient, and the judgment of the prescribing physician. Theproportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

Labeled Compounds and Assay Methods

Another aspect of the present invention relates to labeled compounds ofthe disclosure (radio-labeled, fluorescent-labeled, etc.) that would beuseful not only in imaging techniques but also in assays, both in vitroand in vivo, for localizing and quantitating HPK1 protein in tissuesamples, including human, and for identifying HPK1 ligands by inhibitionbinding of a labeled compound. Substitution of one or more of the atomsof the compounds of the present disclosure can also be useful ingenerating differentiated ADME (Adsorption, Distribution, Metabolism andExcretion). Accordingly, the present invention includes HPK1 bindingassays that contain such labeled or substituted compounds.

The present disclosure further includes isotopically-labeled compoundsof the disclosure. An “isotopically” or “radio-labeled” compound is acompound of the disclosure where one or more atoms are replaced orsubstituted by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). Suitable radionuclides that may be incorporated incompounds of the present disclosure include but are not limited to ²H(also written as D for deuterium), ³H (also written as T for tritium),¹¹C, ¹³C, ¹⁴C N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br, ⁷⁶Br,⁷⁷Br, ¹²³I, ¹²⁴I ¹²⁵I and ¹³¹I. For example, one or more hydrogen atomsin a compound of the present disclosure can be replaced by deuteriumatoms (e.g., one or more hydrogen atoms of a C₁₋₆ alkyl group of Formula(I) can be optionally substituted with deuterium atoms, such as—CD₃being substituted for —CH₃). In some embodiments, alkyl groups inFormula (I) can be perdeuterated.

One or more constituent atoms of the compounds presented herein can bereplaced or substituted with isotopes of the atoms in natural ornon-natural abundance. In some embodiments, the compound includes atleast one deuterium atom. In some embodiments, the compound includes twoor more deuterium atoms. In some embodiments, the compound includes 1-2,1-3, 1-4, 1-5, or 1-6 deuterium atoms. In some embodiments, all of thehydrogen atoms in a compound can be replaced or substituted by deuteriumatoms.

Synthetic methods for including isotopes into organic compounds areknown in the art (Deuterium Labeling in Organic Chemistry by Alan F.Thomas (New York, N.Y., Appleton-Century-Crofts, 1971; The Renaissanceof H/D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and JochenZimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistryof Isotopic Labelling by James R. Hanson, Royal Society of Chemistry,2011). Isotopically labeled compounds can be used in various studiessuch as NMR spectroscopy, metabolism experiments, and/or assays.

Substitution with heavier isotopes, such as deuterium, may affordcertain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances. (seee.g., A. Kerekes et. al. J. Med. Chem. 2011, 54, 201-210; R. Xu et. al.J. Label Compd. Radiopharm. 2015, 58, 308-312). In particular,substitution at one or more metabolism sites may afford one or more ofthe therapeutic advantages.

The radionuclide that is incorporated in the instant radio-labeledcompounds will depend on the specific application of that radio-labeledcompound. For example, for in vitro adenosine receptor labeling andcompetition assays, compounds that incorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I,¹³¹I, or ³⁵S can be useful. For radio-imaging applications ¹¹C, ¹⁸F,¹²⁵I, ¹²³I, ¹²⁴I, ¹³¹I, ⁷⁵Br, ⁷⁶Br, or ⁷⁷Br can be useful.

It is understood that a “radio-labeled” or “labeled compound” is acompound that has incorporated at least one radionuclide. In someembodiments, the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵I, ³⁵S, and ⁸²Br.

The present disclosure can further include synthetic methods forincorporating radio-isotopes into compounds of the disclosure. Syntheticmethods for incorporating radio-isotopes into organic compounds are wellknown in the art, and an ordinary skill in the art will readilyrecognize the methods applicable for the compounds of disclosure.

Alabeled compound of the invention can be used in a screening assay toidentify and/or evaluate compounds. For example, a newly synthesized oridentified compound (i.e., test compound) which is labeled can beevaluated for its ability to bind a HPK1 protein by monitoring itsconcentration variation when contacting with the HPK1, through trackingof the labeling. For example, a test compound (labeled) can be evaluatedfor its ability to reduce binding of another compound which is known tobind to a HPK1 protein (i.e., standard compound). Accordingly, theability of a test compound to compete with the standard compound forbinding to the HPK1 protein directly correlates to its binding affinity.Conversely, in some other screening assays, the standard compound islabeled and test compounds are unlabeled. Accordingly, the concentrationof the labeled standard compound is monitored in order to evaluate thecompetition between the standard compound and the test compound, and therelative binding affinity of the test compound is thus ascertained.

Kits

The present disclosure also includes pharmaceutical kits useful, e.g.,in the treatment or prevention of diseases or disorders associated withthe activity of HPK1, such as cancer or infections, which include one ormore containers containing a pharmaceutical composition comprising atherapeutically effective amount of a compound of Formula (I), or any ofthe embodiments thereof. Such kits can further include one or more ofvarious conventional pharmaceutical kit components, such as, e.g.,containers with one or more pharmaceutically acceptable carriers,additional containers, etc., as will be readily apparent to thoseskilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, canalso be included in the kit.

The following abbreviations may be used herein: AcOH (acetic acid); Ac₂O(acetic anhydride); aq. (aqueous); atm. (atmosphere(s)); Boc(t-butoxycarbonyl); BOP((benzotriazol-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophosphate); br (broad); Cbz (carboxybenzyl); calc.(calculated); d (doublet); dd (doublet of doublets); DBU(1,8-diazabicyclo[5.4.0]undec-7-ene); DCM (dichloromethane); DIAD (N,N′-diisopropyl azidodicarboxylate); DIEA (N,N-diisopropylethylamine);DIPEA (N, N-diisopropylethylamine); DIBAL (diisobutylaluminium hydride);DMF (N, N-dimethylformamide); Et (ethyl); EtOAc (ethyl acetate); FCC(flash column chromatography); g (gram(s)); h (hour(s)); HATU (N, N, N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate);HCl (hydrochloric acid); HPLC (high performance liquid chromatography);Hz (hertz); J (coupling constant); LCMS (liquid chromatography—massspectrometry); LDA (lithium diisopropylamide); m (multiplet); M (molar);mCPBA (3-chloroperoxybenzoic acid); MS (Mass spectrometry); Me (methyl);MeCN (acetonitrile); MeOH (methanol); mg (milligram(s)); min.(minutes(s)); mL (milliliter(s)); mmol (millimole(s)); N (normal); nM(nanomolar); NMP (N-methylpyrrolidinone); NMR (nuclear magneticresonance spectroscopy); OTf (trifluoromethanesulfonate); Ph (phenyl);pM (picomolar); RP-HPLC (reverse phase high performance liquidchromatography); r.t. (room temperature), s (singlet); t (triplet ortertiary); TBS (tert-butyldimethylsilyl); tert (tertiary); tt (tripletof triplets); TFA (trifluoroacetic acid); THF (tetrahydrofuran); μg(microgram(s)); μL (microliter(s)); μM (micromolar); wt % (weightpercent).

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results. The compounds of the Examples have been found to inhibitthe activity of HPK1 according to at least one assay described herein.

EXAMPLES

Experimental procedures for compounds of the invention are providedbelow. Preparatory LC-MS purifications of some of the compounds preparedwere performed on Waters mass directed fractionation systems. The basicequipment setup, protocols, and control software for the operation ofthese systems have been described in detail in the literature. See e.g.“Two-Pump At Column Dilution Configuration for Preparative LC-MS”, K.Blom, J. Combi. Chem., 4, 295 (2002); “Optimizing Preparative LC-MSConfigurations and Methods for Parallel Synthesis Purification”, K.Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi.Chem., 5, 670 (2003); and “Preparative LC-MS Purification: ImprovedCompound Specific Method Optimization”, K. Blom, B. Glass, R. Sparks, A.Combs, J. Combi. Chem., 6, 874-883 (2004). The compounds separated weretypically subjected to analytical liquid chromatography massspectrometry (LCMS) for purity check.

The compounds separated were typically subjected to analytical liquidchromatography mass spectrometry (LCMS) for purity check under thefollowing conditions: Instrument; Agilent 1100 series, LC/MSD, Column:Waters Sunfire™ C₁₈ 5 μm particle size, 2.1×5.0 mm, Buffers: mobilephase A: 0.025% TFA in water and mobile phase B: acetonitrile; gradient2% to 80% of B in 3 minutes with flow rate 2.0 mL/minute.

Some of the compounds prepared were also separated on a preparativescale by reverse-phase high performance liquid chromatography (RP-HPLC)with MS detector or flash chromatography (silica gel) as indicated inthe Examples. Typical preparative reverse-phase high performance liquidchromatography (RP-HPLC) column conditions are as follows:

pH=2 purifications: Waters Sunfire™ C₁₈ 5 μm particle size, 19×100 mmcolumn, eluting with mobile phase A: 0.1% TFA (trifluoroacetic acid) inwater and mobile phase B: acetonitrile; the flow rate was 30 mL/minute,the separating gradient was optimized for each compound using theCompound Specific Method Optimization protocol as described in theliterature [see “Preparative LCMS Purification: Improved CompoundSpecific Method Optimization”, K. Blom, B. Glass, R. Sparks, A. Combs,J. Comb. Chem., 6, 874-883 (2004)]. Typically, the flow rate used withthe 30×100 mm column was 60 mL/minute. pH=10 purifications: WatersXBridge C₁₈ 5 μm particle size, 19×100 mm column, eluting with mobilephase A: 0.15% NH₄OH in water and mobile phase B: acetonitrile; the flowrate was 30 mL/minute, the separating gradient was optimized for eachcompound using the Compound Specific Method Optimization protocol asdescribed in the literature [See “Preparative LCMS Purification:Improved Compound Specific Method Optimization”, K. Blom, B. Glass, R.Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)]. Typically, theflow rate used with 30×100 mm column was 60 mL/minute.”

Intermediate 1. (R)-tert-Butyl1-(2-methyl-5-nitrobenzo[d]thiazol-4-yl)pyrrolidin-3-ylcarbamate

Step 1. (R)-tert-Butyl1-(2-amino-3-fluoro-6-nitrophenyl)pyrrolidin-3-ylcarbamate

A mixture of 2,6-difluoro-3-nitroaniline (2.0 g, 11.5 mmol), tert-butyl(R)-pyrrolidin-3-ylcarbamate (2.57 g, 13.8 mmol), triethylamine (1.9 ml,14 mmol), and 2-methoxyethanol (15.3 mL) was stirred at 160° C. for 20minutes. After cooling to r.t., the reaction mixture was diluted withwater and extracted with CH₂Cl₂. The combined organic phases were driedover MgSO₄, concentrated, and the crude product obtained was purified byBiotage Isolera™. LCMS calculated for C₁₅H₂₂FN₄O₄ (M+H)⁺: m/z=341.2;Found: 341.2.

Step 2. (R)-tert-Butyl1-(2-acetamido-3-fluoro-6-nitrophenyl)pyrrolidin-3-ylcarbamate

A mixture of tert-butyl(R)-(1-(2-amino-3-fluoro-6-nitrophenyl)pyrrolidin-3-yl)carbamate (2.282g, 6.70 mmol), pyridine (0.60 mL, 7.4 mmol), and acetic anhydride (0.70mL, 7.4 mmol) was purged with nitrogen and stirred at 130° C. for 12hrs. After cooling to r.t., the reaction mixture was poured into icewater and the resulting precipitate was filtered, washed with water, anddissolved in EtOAc. The EtOAc solution was then dried over MgSO₄, andconcentrated. The crude product obtained was used directly in the nextstep without further purification. LCMS calculated for C₁₇H₂₄FN₄O₅(M+H)⁺: m/z=383.2; Found: 383.1.

Step 3. (R)-tert-Butyl1-(2-methyl-5-nitrobenzo[d]thiazol-4-yl)pyrrolidin-3-ylcarbamate

A vial was charged with (R)-tert-butyl1-(2-acetamido-3-fluoro-6-nitrophenyl)pyrrolidin-3-ylcarbamate (1.2 g,3.14 mmol), Lawesson's reagent (1.27 g, 3.14 mmol), and THF (15.7 mL).The reaction mixture was purged with nitrogen, sealed, and heated to 75°C. overnight. The reaction mixture was diluted with water, transferredto a separatory funnel with EtOAc, and extracted with CH₂Cl₂. Thecombined organic phases were dried over MgSO₄, concentrated under vacuumand purified by Biotage Isolera™. LCMS calculated for C₁₇H₂₃N₄O₄S(M+H)⁺: m/z=379.1; Found: 379.1.

Intermediate 2. (R)-tert-Butyl1-(5-(2-chloropyrimidine-4-carboxamido)-2-methylbenzo[d]thiazol-4-yl)pyrrolidin-3-ylcarbamate

Step 1. (R)-tert-Butyl1-(5-amino-2-methylbenzo[d]thiazol-4-yl)pyrrolidin-3-ylcarbamate

A mixture of tert-butyl(R)-(1-(2-methyl-5-nitrobenzo[d]thiazol-4-yl)pyrrolidin-3-yl)carbamate(Intermediate 1, 382 mg, 1.01 mmol), iron (643 mg, 11.5 mmol) andammonium chloride (566 mg, 10.6 mmol) in THE (2 mL), MeOH (2 mL), andwater (2 mL) was stirred at 60° C. for 1 hr. After cooling to r.t.,water and NaOH (1 mL of 50% aq. soln) were added and the mixture wasextracted with CH₂Cl₂. The combined organic phases were washed withsaturated NaCl solution, dried over MgSO₄, and concentrated. The crudeproduct obtained was used directly in the next step without furtherpurification. LCMS calculated for C₁₇H₂₅N₄O₂S (M+H)⁺: m/z=349.2; Found:349.2.

Step 2. (R)-tert-Butyl1-(5-(2-chloropyrimidine-4-carboxamido)-2-methylbenzo[d]thiazol-4-yl)pyrrolidin-3-ylcarbamate

HATU (384 mg, 1.0 mmol) was added to a mixture of tert-butyl(R)-(1-(5-amino-2-methylbenzo[d]thiazol-4-yl)pyrrolidin-3-yl)carbamate(from step 1), 2-chloropyrimidine-4-carboxylic acid (160 mg, 1.01 mmol),and triethylamine (306 mg, 3.03 mmol) in DMF (1 mL) and the reactionmixture was stirred at 50° C. for 1 hr. After cooling to r.t., water wasadded and the precipitated product was collected via filtration, washedwith water, and air dried. The crude product obtained was used directlyin the next step without further purification. LCMS calculated forC₂₂H₂₆ClN₆O₃S (M+H)⁺: m/z=489.1; Found: 489.1.

Intermediate 3. tert-Butyl3-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl(methyl)carbamate

Step 1. 4-Bromo-3-fluoro-5-methylaniline

N-Bromosuccinimide (15.8 g, 89 mmol) was added to a solution of3-fluoro-5-methylaniline (11 g, 88 mmol) in DMF (80 mL) and cooled to 0°C. in an ice bath. The reaction mixture was stirred at 0° C. for 30minutes. After warming to r.t., the reaction was stirred for anadditional 1 hr. Water and EtOAc were then added, and the organic phasewas washed with saturated aqueous NaHCO₃ and saturated aqueous NaClsolution. The organic phase was then dried over magnesium sulfate andthe solvents were evaporated under reduced pressure. The crude productwas purified by Biotage Isolera™ (17.2 g, 96%). LCMS calculated forC₇H₈BrFN (M+H)⁺ m/z=203.9; found 204.0.

Step 2. 2-Bromo-1-fluoro-5-iodo-3-methylbenzene

A solution of 4-bromo-3-fluoro-5-methylaniline (7.28 g, 36 mmol) inacetonitrile (190 mL) cooled to 0° C. in an ice bath was treated withsulfuric acid (4.75 mL, 89 mmol) dissolved in H₂O (10 mL). Afterstirring for 5 minutes, a solution of sodium nitrite (4.92 g, 71.4 mmol)in water (10 mL) was added dropwise and the reaction mixture was stirredfor an additional 15 minutes at 0° C. Potassium iodide (23.7 g, 143mmol) in water (20 mL) was then added, and the ice-bath was removed.After warming to r.t. the reaction mixture was stirred for an additional20 minutes before the reaction was treated with aqueous Na₂S₂O₃solution. The mixture was then extracted with ethyl acetate and thecombined organic phases were washed with saturated aqueous NaClsolution, dried over magnesium sulfate, and concentrated under reducedpressure. The crude product was purified by Biotage Isolera™ (10.3 g,94%). ¹H NMR (400 MHz, CDCl₃) δ 7.39 (br s, 1H), 7.29 (m, 1H), 2.38 (s,3H) ppm.

Step 3.2-Bromo-1-fluoro-3-methyl-5-vinylbenzene

A solution of 2-bromo-1-fluoro-5-iodo-3-methylbenzene (10.3 g, 32.8mmol) in 1,4-dioxane (80 mL) and water (13.3 mL) was treated with4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (Aldrich, 6.16 mL, 34.5mmol), [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II)(Pd(dppf)Cl₂) (2.40 g, 3.3 mmol), and potassium phosphate tribasic (13.9g, 65.7 mmol). The reaction mixture was degassed, backfilled withnitrogen, and heated to 70° C. for 1 h. After cooling to r.t. thereaction mixture was filtered over a pad of Celite. The filtrate wasdiluted with water and extracted with ethyl acetate. The combinedorganic phases were washed with saturated aqueous NaCl solution, driedover magnesium sulfate, and concentrated under reduced pressure. Thecrude product was purified by Biotage Isolera™ (5.46 g, 77%). ¹H NMR(400 MHz, CDCl₃) δ 7.05 (br s, 1H), 7.01 (dd, J=2.0, 9.4 Hz, 1H), 6.60(dd, J=10.9, 17.5 Hz, 1H), 5.75 (d, J=17.5 Hz, 1H), 5.31 (d, J=10.9 Hz,1H), 2.42 (s, 3H) ppm.

Step 4. 4-Bromo-3-fluoro-5-methylbenzaldehyde

A solution of 2-bromo-1-fluoro-3-methyl-5-vinylbenzene (5.46 g, 25.4mmol) in acetone (46 mL) and water (4.6 mL) was sequentially treatedwith sodium periodate (21.7 g, 102 mmol) and a 4% aqueous solution ofosmium tetroxide (8.07 mL, 1.27 mmol). The reaction mixture was stirredat r.t. for 2 h. The reaction mixture was then filtered over a pad ofCelite. The filtrate was diluted with water and extracted with ethylacetate. The combined organic phases were washed with saturated aqueousNaCl solution, dried over magnesium sulfate, and concentrated underreduced pressure. The crude product was purified by Biotage Isolera™(3.22 g, 58%). ¹H NMR (400 MHz, CDCl₃) δ 9.93 (d, J=1.8 Hz, 1H), 7.55(d, J=1.8 Hz, 1H), 7.44 (dd, J=1.8, 7.8 Hz, 1H), 2.52 (s, 3H) ppm.

Step 5. 1-(4-Bromo-3-fluoro-5-methylphenyl)-N-methylmethanamine

A solution of 4-bromo-3-fluoro-5-methylbenzaldehyde (1.46 g, 6.70 mmol)in MeOH (6.70 mL), was placed under a nitrogen environment. The solutionwas treated with 33% solution of methanamine (3.15 g, 33.5 mmol) inethanol and titanium(IV) isopropoxide (0.982 mL, 3.35 mmol), and thereaction mixture was stirred at r.t. for 3 hrs. Sodium borohydride (1.01g, 26.8 mmol) was then added to the reaction mixture portion wise, andstirring was continued at r.t. for an additional 1.5 hrs. NH₄OH (30%aqueous solution) was added to the reaction mixture and stirringcontinued for another 15 minutes. The reaction mixture was thenacidified with 1 N HCl and extracted with ethyl acetate. The aqueousphase was made basic and extracted with ethyl acetate. The combinedorganic phases were washed with saturated aqueous NaCl solution, driedover magnesium sulfate, and concentrated under reduced pressure toafford 1-(4-bromo-3-fluoro-5-methylphenyl)-N-methylmethanamine (1.32 g,85%) as a light yellow oil. The crude product was used in the next stepwithout further purification. LCMS calculated for C₉H₁₂BrFN (M+H)⁺m/z=232.0; found 231.9.

Step 6. tert-Butyl 4-bromo-3-fluoro-5-methylbenzyl(methyl)carbamate

A solution of 1-(4-bromo-3-fluoro-5-methylphenyl)-N-methylmethanamine(1.32 g, 5.67 mmol) and triethylamine (1.58 mL, 11.34 mmol) in THE (18.9mL) was treated with di-tert-butyl dicarbonate (1.58 mL, 6.80 mmol). Thereaction mixture was then stirred at ambient temperature for 1 hr. Thereaction mixture was then diluted with water and extracted with ethylacetate. The combined organic phases were dried with magnesium sulfateand concentrated under reduced pressure. The crude product was purifiedby Biotage Isolera™ (1.42 g, 78%). LCMS calculated for CioHi₂BrFNO₂(M+H-C₄H₈)⁺ m/z=276.0; found 276.0.

Step 7. tert-Butyl3-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl(methyl)carbamate

A solution of tert-butyl(4-bromo-3-fluoro-5-methylbenzyl)(methyl)carbamate (573 mg, 1.73 mmol)in THF (11.5 mL) was cooled to −78° C. in a dry ice/acetone bath andBuLi (1.6 M solution in hexanes, 1.19 mL, 1.90 mmol) was added dropwise.The reaction mixture was then allowed to stir for 3 minutes before2-isopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (427 μL, 2.25 mmol)was added dropwise. The mixture was warmed to r.t and stirred for anadditional 5 hrs. The reaction mixture was then treated with water,acidified to pH 5-6 using 1 N HCl, and extracted with ethyl acetate. Thecombined organic phases were washed with saturated aqueous NaClsolution, dried over magnesium sulfate, and concentrated to affordtert-butyl3-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl(methyl)carbamate(679 mg, quantitative yield). The crude product was used in the nextstep without further purification. LCMS calculated for C₁₆H₂₄BrFNO₄(M+H-C₄H₈)⁺ m/z=324.2; found 324.1.

Intermediate 4. 2-(2-Fluoro-6-methoxyphenyl)pyrimidine-4-carboxylic acid

A mixture of 2-chloropyrimidine-4-carboxylic acid (10.1 g, 63.7 mmol),(2-fluoro-6-methoxyphenyl)boronic acid (24 g, 141 mmol), XPhos Pd G2(2.50 g, 3.18 mmol), and potassium phosphate tribasic (27.0 g, 127 mmol)was treated with 1,4-dioxane (100 mL) and water (20 mL). The reactionmixture was sparged with nitrogen for 5 minutes and stirred at 80° C.overnight. The mixture was then cooled to r.t., filtered over a pad ofCelite, diluted with water and extracted with CH₂Cl₂. The aqueous phasewas separated and then acidified via the addition of 1N HCl. Theresulting solid was collected by filtration, washed with water and airdried. LCMS calculated for C₁₂H₁₀FN₂O₃ (M+H)⁺: m/z=249.1; found 249.1.

Intermediate 5. (S)-tert-Butyl1-(2-methyl-5-nitrobenzo[d]thiazol-4-yl)pyrrolidin-3-ylcarbamate

This compound was prepared according to a modified procedure describedfor Intermediate 1, using tert-butyl (S)-pyrrolidin-3-ylcarbamateinstead of tert-butyl (R)-pyrrolidin-3-ylcarbamate as starting material.LCMS calculated for C₁₇H₂₃N₄O₄S (M+H)⁺: m/z=379.1; Found: 379.1.

Intermediate 6. (S)-tert-butyl1-(7-bromo-2-methyl-5-nitrobenzo[d]thiazol-4-yl)pyrrolidin-3-ylcarbamate

A mixture of (S)-tert-butyl1-(2-methyl-5-nitrobenzo[d]thiazol-4-yl)pyrrolidin-3-ylcarbamate(Intermediate 5, 710 mg, 1.88 mmol), N-bromosuccinimide (668 mg, 3.75mmol), and DMF (10 mL) was heated to 80° C. for 1 h. The mixture wascooled to r.t., and Boc-anhydride (0.44 mL, 1.9 mmol) and triethylamine(0.26 mL, 1.9 mmol) were added. The reaction was stirred at r.t. for 2h, diluted with CH₂Cl₂, water, and saturated aqueous NaHCO₃ solution.The mixture was then extracted with CH₂Cl₂, the combined organic phaseswere dried over MgSO₄, filtered, concentrated, and purified by BiotageIsolera™ to afford (S)-tert-butyl1-(7-bromo-2-methyl-5-nitrobenzo[d]thiazol-4-yl)pyrrolidin-3-ylcarbamate(510 mg, 59%) as an orange solid. LCMS calculated for C₁₇H₂₂BrN₄O₄S(M+H)⁺: m/z=457.1; Found: 457.0.

Intermediate 7. (S)-tert-Butyl(1-(3-fluoro-2-(2-methoxyacetamido)-6-nitrophenyl)pyrrolidin-2-yl)methylcarbamate

Step 1. (S)-tert-Butyl(1-(2-amino-3-fluoro-6-nitrophenyl)pyrrolidin-2-yl)methylcarbamate

A mixture of (S)-tert-butyl pyrrolidin-2-ylmethylcarbamate (2.4 g, 12.0mmol), 2,6-difluoro-3-nitroaniline (2.0 g, 11.5 mmol), 2-methoxyethanol(15 mL), and triethylamine (3 mL, 21.5 mmol) was stirred at 120° C.overnight. The mixture was then cooled to r.t., diluted with water andextracted with CH₂Cl₂. The combined organic phases were dried overMgSO₄, concentrated, and the crude product obtained was purified byBiotage Isolera™ to afford tert-butyl(S)-((1-(2-amino-3-fluoro-6-nitrophenyl)pyrrolidin-2-yl)methyl)carbamate(1.51 g, 37% yield) as an orange oil. LCMS calculated for C₁₆H₂₄FN₄O₄(M+H)⁺: m/z=355.2; Found: 355.1.

Step 2.(S)-tert-Butyl(1-(3-fluoro-2-(2-methoxyacetamido)-6-nitrophenyl)pyrrolidin-2-yl)methylcarbamate

A mixture of 2-methoxyacetic acid (0.3 mL, 3.9 mmol) and DMF (10 mg,0.14 mmol) in anhydrous CH₂Cl₂ (1.5 mL) was cooled in an ice bath andtreated dropwise with oxalyl chloride (0.3 mL, 3.4 mmol). The ice bathwas removed, the reaction mixture was stirred at r.t. for 1 hr and thentreated with a mixture of (S)-tert-butyl(1-(2-amino-3-fluoro-6-nitrophenyl)pyrrolidin-2-yl)methylcarbamate (250mg, 0.705 mmol) and triethylamine (0.2 mL, 1.4 mmol) in anhydrous CH₂Cl₂(1.5 mL). The resulting reaction mixture was stirred at r.t. for 2 hrs,diluted with water and extracted with CH₂Cl₂. The combined organicphases were dried over MgSO4 and concentrated. The crude productobtained was used in the next step without further purification. LCMScalculated for C₁₉H₂₇FN₄O₆Na (M+Na)⁺: m/z=449.2; Found: 449.1.

Intermediate 8.(S)-tert-Butyl(1-(3-fluoro-2-(3-methoxypropanamido)-6-nitrophenyl)pyrrolidin-2-yl)methylcarbamate

This compound was prepared according to the procedures described inIntermediate 7, using 3-methoxypropanoic acid instead of 2-methoxyaceticacid as starting material. LCMS calculated for C₂₀H₂₉FN₄O₆Na (M+Na)⁺:m/z=463.2; Found: 463.1.

Intermediate 9. 4-Chloro-2-methyl-5-nitrobenzo[d]thiazole

Step 1. N-(2-Chloro-6-fluorophenyl)acetamide

Acetic anhydride (10 mL, 106 mmol) was added to a solution of2-chloro-6-fluoroaniline (12.81 g, 88 mmol) in AcOH (44 mL) and themixture was stirred at 90° C. for 2 hrs. After cooling to r.t., waterwas added and the solid precipitate was collected by filtration, washedwith water, and air dried to afford N-(2-chloro-6-fluorophenyl)acetamide(16.2 g, 98% yield) as a white solid. The crude product obtained wasused directly in the next step without further purification. LCMScalculated for C₈H₈ClFNO (M+H)⁺: m/z=188.0; Found 188.0.

Step 2. N-(2-Chloro-6-fluoro-3-nitrophenyl)acetamide

A mixture of N-(2-chloro-6-fluorophenyl)acetamide (16.2 g, 87 mmol) inH₂SO₄ (43 mL) was cooled in an acetone/ice bath and treated with nitricacid (4.6 mL, 103 mmol) dropwise. The mixture was stirred for 2 hrs. Itwas then carefully poured into an ice/water mixture, and the solidprecipitate was collected by filtration, washed with water, and airdried to afford N-(2-chloro-6-fluoro-3-nitrophenyl)acetamide (10.4 g,44.7 mmol, 52% yield) as an off-white solid. The crude product obtainedwas used directly in the next step without further purification. LCMScalculated for C₈H₇ClFN₂O₃ (M+H)⁺: m/z=233.0; Found 233.1.

Step 3. 4-chloro-2-methyl-5-nitrobenzo[d]thiazole

A mixture of N-(2-chloro-6-fluoro-3-nitrophenyl)acetamide (1.26 g, 5.42mmol) and sodium bicarbonate (0.910 g, 10.83 mmol) in dry DMF (50 ml)was cooled in an ice bath before sodium sulfide (0.423 g, 5.42 mmol) wasadded. The ice bath was removed and the mixture was stirred for 15minutes. Water was then added and the mixture was extracted with CH₂Cl₂.The combined organic phases were dried over MgSO₄, concentrated andpurified by Biotage Isolera™ to afford4-chloro-2-methyl-5-nitrobenzo[d]thiazole as a yellow solid. LCMScalculated for C₈H₆ClN₂O₂S (M+H)⁺: m/z=229.0; Found 228.9.

Intermediate 10.tert-Butyl(3R,5S)-1-(5-Amino-2-methylbenzo[d]thiazol-4-yl)-5-(hydroxymethyl)pyrrolidin-3-ylcarbamate

Step 1.tert-Butyl(3R,5S)-5-(hydroxymethyl)-1-(2-methyl-5-nitrobenzo[d]thiazol-4-yl)pyrrolidin-3-ylcarbamate

A mixture of 4-chloro-2-methyl-5-nitrobenzo[d]thiazole (Intermediate 9,748 mg, 3.27 mmol) in DMSO (4 mL) was treated with tert-butyl((3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate (778 mg, 3.60 mmol)and triethylamine (1 mL, 7.17 mmol), and the reaction mixture wasstirred at 120° C. for 4 hrs. After cooling to r.t., water was added andthe mixture was stirred at r.t. overnight. The precipitated product wasthen collected via filtration, washed with water, and air dried. Theresultant crude product was used in the next step without furtherpurification. LCMS calculated for C₁₈H₂₅N₄O₅S (M+H)⁺: m/z=409.2; Found409.2.

Step 2. tert-Butyl(3R,5S)-1-(5-amino-2-methylbenzo[d]thiazol-4-yl)-5-(hydroxymethyl)pyrrolidin-3-ylcarbamate

A mixture of tert-butyl((3R,5S)-5-(hydroxymethyl)-1-(2-methyl-5-nitrobenzo[d]thiazol-4-yl)pyrrolidin-3-yl)carbamate(1.26 g, 3.08 mmol, 94% yield) (from step 1), iron (1096 mg, 19.63mmol), and ammonium chloride (1400 mg, 26.2 mmol) in THF (4 mL), MeOH (4mL), and water (4 mL) was stirred at 60° C. for 1 hr. After cooling tor.t., the reaction mixture was filtered through a plug of Celite,diluted with water, and extracted with CH₂Cl₂. The combined organicphases were dried over MgSO₄ and the solvents were concentrated undervacuum. The obtained crude product was used in the next step withoutfurther purification. LCMS calculated for C₁₈H₂₇N₄O₃S (M+H)⁺: m/z=379.2;Found 379.1.

Intermediate 11. 4-Chloro-2-ethyl-5-nitrobenzo[d]thiazole

Step 1. N-(2-Chloro-6-fluorophenyl)propionamide

A mixture of 2-chloro-6-fluoroaniline (2.23 g, 15.32 mmol) in propionicacid (7.66 ml) was treated with propionic anhydride (2.369 ml, 18.38mmol), and the reaction mixture was stirred at 90° C. for 1 h. Aftercooling to r.t., water was added and the solid precipitate was collectedby filtration, washed with water, and air dried. The crude productobtained was used directly in the next step without furtherpurification. LCMS calculated for C₉H₁₀ClFNO (M+H)⁺: m/z=202.0; Found202.1.

Step 2. N-(2-Chloro-6-fluoro-3-nitrophenyl)propionamide

A mixture of N-(2-chloro-6-fluorophenyl)propionamide (3.09 g, 15.3 mmol)in H₂SO₄ (5 mL) was cooled in an ice bath, treated with nitric acid(0.856 ml, 19.16 mmol) dropwise and stirred at 0° C. for 30 minutes. Theice bath was removed and the mixture was stirred at r.t. for 30 minutes,and heated at 50° C. for 45 minutes. After cooling to r.t., the mixturewas poured into an ice/water mixture and the product was extracted withCH₂Cl₂. The combined organic phases were dried over MgSO₄, concentratedto about 30 mL, and diluted with hexanes until a solid precipitates out.The solid precipitate was then collected by filtration and air dried.The crude product obtained was used directly in the next step withoutfurther purification. LCMS calculated for C₉H₉ClFN₂O₃ (M+H)⁺: m/z=247.0;Found 247.0.

Step 3. 4-Chloro-2-ethyl-5-nitrobenzo[d]thiazole

A mixture of N-(2-chloro-6-fluoro-3-nitrophenyl)propionamide (632 mg,2.56 mmol) and Lawesson's reagent (777 mg, 1.922 mmol in THF (5 mL) waspurged under nitrogen and stirred at 60° C. overnight. After cooling tor.t., the reaction mixture was concentrated and the crude residue waspurified by Biotage Isolera™. LCMS calculated for C₉HClN₂O₂S (M+H)⁺:m/z=243.0; Found 243.0.

Intermediate 12. 4-Chloro-2-isopropyl-5-nitrobenzo[d]thiazole

Step 1. N-(2-Chloro-6-fluorophenyl)isobutyramide

A mixture of 2-chloro-6-fluoroaniline (1.5 g, 10.3 mmol), pyridine (1.0mL, 12.4 mmol), and isobutyric anhydride (2.0 mL, 12.1 mmol) was purgedwith nitrogen and irradiated in a microwave reactor at 150° C. for 2hrs. After cooling to r.t., water was added and the mixture was stirreduntil a solid precipitate formed. The resulting solid was then collectedby filtration, washed with water, and air dried to affordN-(2-chloro-6-fluorophenyl)isobutyramide in quantitative yield as anoff-white solid. The crude product obtained was used directly in thenext step without further purification. LCMS calculated for C₁₀H₁₂ClFNO(M+H)⁺: m/z=216.1; Found 216.1.

Step 2. N-(2-Chloro-6-fluoro-3-nitrophenyl)isobutyramide

A mixture of N-(2-chloro-6-fluorophenyl)isobutyramide (2.22 g, 10.29mmol) in H₂SO₄ (3 mL) was cooled in an ice bath, treated with nitricacid (0.575 ml, 12.87 mmol) dropwise and stirred at 0° C. for 30minutes. The ice bath was removed and the mixture was stirred at r.t.for 30 minutes, and heated at 50° C. for 45 minutes. After cooling tor.t., the mixture was poured into an ice/water mixture and the productwas extracted with CH₂Cl₂. The combined organic phases were dried overMgSO₄, concentrated to about 30 mL, and diluted with hexanes until asolid precipitated out. The solid precipitate was then collected byfiltration and air dried. The crude product obtained was used directlyin the next step without further purification. LCMS calculated forC₁₀H₁₁ClFN₂O₃ (M+H)⁺: m/z=261.0; Found 261.0.

Step 3. 4-chloro-2-isopropyl-5-nitrobenzo[d]thiazole

A mixture of N-(2-chloro-6-fluoro-3-nitrophenyl)isobutyramide (582 mg,2.23 mmol) and Lawesson's reagent (677 mg, 1.68 mmol) in THE (5 mL) waspurged under nitrogen and stirred at 60° C. overnight. After cooling tor.t., the reaction mixture was concentrated and the crude residue waspurified by Biotage Isolera™. LCMS calculated for C₁₀H₁₀ClN₂O₂S (M+H)⁺:m/z=257.0; Found 256.9.

Intermediate 13. tert-Butyl(3R,5S)-1-(5-(2-chloropyrimidine-4-carboxamido)-2-methylbenzo[d]thiazol-4-yl)-5-(hydroxymethyl)pyrrolidin-3-ylcarbamate

Step 1. tert-Butyl(3R,5S)-5-(hydroxymethyl)-1-(2-methyl-5-nitrobenzo[d]thiazol-4-yl)pyrrolidin-3-ylcarbamate

A mixture of 4-chloro-2-methyl-5-nitrobenzo[d]thiazole (Intermediate 9,447 mg, 1.96 mmol) in DMSO (4 mL) was treated with tert-butyl((3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate (444 mg, 2.053 mmol)and triethylamine (0.8 mL, 5.74 mmol), and the reaction mixture wasstirred at 120° C. for 4 hrs. After cooling to r.t., water was added andthe precipitated product was then collected via filtration, washed withwater, and air dried. The obtained crude product was used in the nextstep without further purification. LCMS calculated for C₁₈H₂₅N₄O₅S(M+H)⁺: m/z=409.2; Found 409.1.

Step 2. tert-Butyl(3R,5S)-1-(5-amino-2-methylbenzo[d]thiazol-4-yl)-5-(hydroxymethyl)pyrrolidin-3-ylcarbamate

A mixture of tert-butyl((3R,5S)-5-(hydroxymethyl)-1-(2-methyl-5-nitrobenzo[d]thiazol-4-yl)pyrrolidin-3-yl)carbamate(from step 1), iron (655 mg, 11.73 mmol), and ammonium chloride (837 mg,15.64 mmol) in THE (4 mL), MeOH (4 mL), and water (4 mL) was stirred at60° C. for 1 hr. After cooling to r.t., the reaction mixture wasfiltered through a plug of Celite, diluted with water, and extractedwith CH₂Cl₂. The combined organic phases were dried over MgSO₄ and thesolvents were concentrated under vacuum. The resultant crude product wasused in the next step without further purification. LCMS calculated forC₁₈H₂₇N₄O₃S (M+H)⁺: m/z=379.2; Found 379.2.

Step 3. tert-butyl(3R,5S)-1-(5-(2-chloropyrimidine-4-carboxamido)-2-methylbenzo[d]thiazol-4-yl)-5-(hydroxymethyl)pyrrolidin-3-ylcarbamate

HATU (595 mg, 1.564 mmol) was added to a solution of tert-butyl((3R,5S)-1-(5-amino-2-methylbenzo[d]thiazol-4-yl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate(from step 2), 2-chloropyrimidine-4-carboxylic acid (248 mg, 1.564mmol), and triethylamine (0.3 mL, 2.15 mmol) in DMF (1 mL). The reactionmixture was stirred at 50° C. for 1 hr before additional HATU (595 mg,1.564 mmol) and 2-chloropyrimidine-4-carboxylic acid (248 mg, 1.564mmol) were added, and the reaction mixture was stirred at 50° C. for anadditional 1 hr. After cooling to r.t., water was added and theprecipitated product was then collected via filtration, washed withwater, and air dried. The resulting solid was then dissolved in THE (2mL) and MeOH (2 mL) and treated with NH₄OH (2 mL) and the reactionmixture was stirred at r.t. for 15 minutes. The mixture was thenconcentrated to half volume, water was added, and the precipitatedproduct was then collected via filtration, washed with water, and airdried. The crude product was used in the next step without furtherpurification. LCMS calculated for C₂₃H₂₈ClN₆O₄S (M+H)⁺: m/z=519.2; Found519.0.

Intermediate 14. 2-(2,3-Difluoro-6-methoxyphenyl)pyrimidine-4-carboxylicacid

A mixture of methyl 2-chloropyrimidine-4-carboxylate (300 mg, 1.738mmol), (3,6-difluoro-2-methoxyphenyl)boronic acid (425 mg, 2.260 mmol),XPhos Pd G2 (68.4 mg, 0.087 mmol) and Hunig's base (607 μl, 3.48 mmol)was treated with 1,4-dioxane (5215 μL) and water (579 μL) and thereaction flask was evacuated, back filled with nitrogen, and thenstirred at 90° C. for 3 hrs. The reaction mixture was then concentratedand purified by Biotage Isolera™ to provide the intermediate. Thisintermediate was then dissolved in a 1:1:1 mixture of THF/water/MeOH,and treated with lithium hydroxide (285 mg, 6.95 mmol) and the reactionmixture heated to 60° C. for 1 hr. 1N HCl was added to neutralize themixture, resulting in the precipitation of the product, which wascollected by filtration and air dried. The obtained crude product wasused in the next step without further purification.

Intermediate 15.2-(3-Cyano-2-fluoro-6-(methoxy-d₃)phenyl)pyrimidine-4-carboxylic acid

Step 1. 2-Fluoro-4-(methoxy-d₃)benzonitrile

A solution of 2-fluoro-4-hydroxybenzonitrile (1.087 g, 7.93 mmol) in DMF(26.4 mL) was treated with potassium carbonate (1.644 g, 11.89 mmol) andiodomethane-d₃ (0.592 mL, 9.51 mmol) and the reaction mixture heated to80° C. for hr. The reaction mixture was then quenched with water andextracted with diethyl ether. The organic phase was washed with waterand saturated aqueous NaCl solution, dried over sodium sulfate andconcentrated. The crude product was used in the next step withoutfurther purification.

Step2.2-Fluoro-4-(methoxy-d3)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

A solution of diisopropylamine (1174 μL, 8.38 mmol) in dry THE (34.9 mL)was cooled −78° C. and treated with nBuLi (3.35 ml, 8.38 mmol) dropwiseand the reaction mixture was stirred at −78° C. for 30 minutes.2-Fluoro-4-(methoxy-d₃)benzonitrile (1.077 g, 6.98 mmol) and HMPA werethen added and the reaction mixture stirred at −78° C. for 1 hr.2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.166 ml, 10.48mmol) was then added and the reaction mixture stirred at −78° C. for 10minutes, then warmed up to r.t. by removing the cooling bath. Thereaction was treated with 1N HCl and extracted with ethyl acetate. Theorganic phase was washed with water and saturated aqueous NaCl solution,dried over sodium sulfate and concentrated. The crude product was usedin the next step without further purification.

Step 3.2-(3-Chloro-2-fluoro-6-(methoxy-d₃)phenyl)pyrimidine-4-carboxylic acid

A solution of2-fluoro-4-(methoxy-d)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile(1560 mg, 5.79 mmol) and Hunig's base (1012 μL, 5.79 mmol) in water(1333 μL) and 1,4-dioxane (12 mL) was treated with methyl2-chloropyrimidine-4-carboxylate (500 mg, 2.90 mmol) and ((t-Bu)₃P)₂Pd(74.0 mg, 0.145 mmol). The reaction flask was evacuated, back filledwith nitrogen, and then stirred at 80° C. overnight. The reactionmixture was then diluted with CH₂Cl₂ and filtered through a plug ofCelite. The filtrate was concentrated and the residue was purified byBiotage Isolera™ to provide the desired intermediate. This intermediatewas then dissolved in a 1:1 mixture of THF/water (4 mL), and treatedwith lithium hydroxide (238 mg, 5.79 mmol) and the reaction mixture wasstirred at 60° C. for 1 hr. The reaction mixture was then acidified topH 1 with 1 N HCl and extracted with ethyl acetate. The organic phasewas washed with saturated aqueous NaCl solution, dried over sodiumsulfate and concentrated. The obtained crude product was used in thenext step without further purification.

Intermediate 16. 2-(2,6-Difluorophenyl)pyrimidine-4-carboxylic acid

This compound was prepared according to the procedures described inIntermediate 4, using2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane insteadof (2-fluoro-6-methoxyphenyl)boronic acid as starting material. LCMScalculated for C₁₁H₇F₂N₂O₂ (M+H)⁺: m/z=237.0; Found: 237.1.

Intermediate 17. tert-Butyl(1S,4S)-5-(5-amino-2-methylbenzo[d]thiazol-4-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate

This compound was prepared according to the procedures described inIntermediate 10, using tert-butyl(1S,4S)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate instead oftert-butyl ((3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate asstarting material. LCMS calculated for C₁₉H₂₇N₄O₂S (M+H)⁺: m/z=375.2;Found: 375.2.

Intermediate 18. tert-Butyl((3R,5S)-1-(2-bromo-5-nitrobenzo[d]thiazol-4-yl)-5-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidin-3-yl)carbamate

Step 1. N-(2-Chloro-6-fluorophenyl)formamide

Acetic anhydride (7.1 ml, 76 mmol) and formic acid (4.09 mL, 103 mmol)were mixed together and stirred at 55° C. for 90 minutes then cooled tor.t. A solution of 2-chloro-6-fluoroaniline (10.0 g, 68.7 mmol) in THF(20 mL) was then added in one portion and stirred at r.t. for another 3hrs. After this time it was concentrated to dryness. The residue wasdissolved in ethyl acetate and washed with saturated sodium bicarbonatesolution. The organic phase was washed with saturated aqueous NaClsolution, dried over MgSO₄, filtered and then concentrated to dryness toafford the crude product which was used for next step withoutpurification. LCMS calculated for C₇H₆ClFNO (M+H)⁺: m/z=174.0; Found:174.0.

Step 2. N-(2-Chloro-6-fluoro-3-nitrophenyl)formamide

The residue from Step 1 was dissolved in sulfuric acid (40 mL, 750 mmol)then cooled to 0° C. Nitric acid (2.76 mL, 61.8 mmol) was added dropwiseover 5 minutes, and the reaction mixture was stirred at 0° C. foranother 30 minutes. The reaction mixture was then poured onto ice waterand extracted with ethyl acetate. The organic phase was dried overMgSO₄, filtered and concentrated to dryness to afford the crude desiredproduct as white solid which was used for the next step withoutpurification. LCMS calculated for C₇H₅ClFN₂O₃ (M+H)⁺: m/z=219.0; Found:219.0.

Step 3. 4-Chloro-5-nitrobenzo[d]thiazole

A solution of the intermediate from Step 2 in DMF (100 mL) was treatedwith sodium sulfide (5.4 g, 68.7 mmol) and the reaction mixture wasstirred at r.t. for 1 hr. After this time it was poured into 1 N HClsolution and diluted with water. The mixture was filtered and the solidwas collected, air dried and purified by silica gel chromatography using0-100% ethyl acetate in hexanes to afford desired product as yellowishsolid. LCMS calculated for C₇H₄CN₂O₂S (M+H)⁺: m/z=215.0; Found: 215.0.

Step 4. tert-Butyl((3R,5S)-5-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidin-3-yl)carbamate

A solution of tert-butyl((3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate (1000 mg, 4.62 mmol)in CH₂Cl₂ (10 ml) was treated with tert-butylchlorodimethylsilane (1394mg, 9.25 mmol) followed by addition of triethylamine (1.933 mL, 13.87mmol). The resulting solution was stirred at r.t. for 1 hr, then dilutedwith CH₂Cl₂ and washed with water and saturated aqueous NaCl solution.The organic phase was dried over MgSO₄, filtered and concentrated todryness to afford the crude intermediate which was used for the nextstep without further purification.

LCMS calculated for C₁₆H₃₅N₂O₃Si (M+H)⁺: m/z=331.2; found 331.2.

Step 5. tert-Butyl((3R,5S)-5-(((tert-butydimethylsilyl)oxy)methyl)-1-(5-nitrobenzo[d]thiazol-4-yl)pyrrolidin-3-yl)carbamate

A solution of intermediate from Step 4 in DMSO (5 ml) was treated with4-chloro-5-nitrobenzo[d]thiazole (1489 mg, 6.94 mmol) and the reactionmixture was stirred at 130° C. for 2 hrs. After this time it was cooledto r.t., diluted with ethyl acetate and washed with water and saturatedaqueous NaCl solution. The organic phase was dried over MgSO₄, filteredand concentrated to dryness. The residue was purified by silica gelchromatography using 0-100% ethyl acetate in hexanes to afford desiredproduct as brownish oil. LCMS calculated for C₂₃H₃₇N₄O₅SSi (M+H)⁺:m/z=509.2; found 509.2.

Step 6. tert-Butyl((3R,5S)-1-(2-bromo-5-nitrobenzo[d]thiazol-4-yl)-5-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidin-3-yl)carbamate

A solution of intermediate from Step 5 (600 mg, 1.18 mmol) in THE (20mL) was treated with LDA, 2.0 M in THE (2.36 mL, 4.72 mmol) dropwise at−20° C. The resulting solution was stirred at that temperature for 10minutes then carbon tetrabromide (1173 mg, 3.54 mmol) solution in THF (1mL) was added. The reaction mixture was then slowly warmed up to r.t.over 30 minutes, then concentrated to dryness. The residue was purifiedby silica gel chromatography using 0-100% ethyl acetate in hexanes toafford desired product as brownish oil. LCMS calculated forC₂₃H₃₆BrN₄O₅SSi (M+H)⁺: m/z=587.0; found 587.0.

Example 1.(R)—N-(4-(3-Aminopyrrolidin-1-yl)-2-methylbenzo[d]thiazol-5-yl)-2-(2,6-difluorophenyl)pyrimidine-4-carboxamide

A solution of tert-butyl(R)-(1-(5-(2-chloropyrimidine-4-carboxamido)-2-methylbenzo[d]thiazol-4-yl)pyrrolidin-3-yl)carbamate(Intermediate 2, 25.2 mg, 0.052 mmol) in 1,4-dioxane (0.7 mL) wastreated with (2,6-difluorophenyl)boronic acid (16.3 mg, 0.103 mmol),XPhos Pd G2 (7.5 mg), potassium phosphate tribasic (21.8 mg, 0.103mmol), and water (0.1 mL). The reaction mixture was then sparged withnitrogen, sealed, and stirred at 80° C. overnight. After cooling tor.t., the reaction mixture was concentrated and TFA (1 mL) was added andthe resulting mixture was stirred at r.t. for 30 minutes. The reactionmixture was then diluted with acetonitrile and purified with prep-LCMS(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated forC₂₃H₂₁F₂N₆OS (M+H)⁺: m/z=467.1; Found 467.2. ¹H NMR (500 MHz, DMSO-d₆) δ11.23 (s, 1H), 9.34 (d, J=5.0 Hz, 1H), 8.55 (d, J=8.8 Hz, 1H), 8.31-8.15(m, 4H), 7.95 (d, J=8.8 Hz, 1H), 7.71 (tt, J=8.4, 6.4 Hz, 1H), 7.39 (t,J=8.4 Hz, 2H), 3.81 (s, 1H), 3.69-3.59 (m, 2H), 3.53 (q, J=8.2 Hz, 1H),3.34-3.24 (m, 1H), 2.85 (s, 3H), 2.24-2.14 (m, 1H), 2.08-1.98 (m, 1H).

Example 2.(R)—N-(4-(3-Aminopyrrolidin-1-yl)-2-methylbenzo[d]thiazol-5-yl)-2-(2-fluoro-6-methylphenyl)pyrimidine-4-carboxamide

This compound was prepared according to the procedures described inExample 1, using (2-fluoro-6-methylphenyl)boronic acid instead of(2,6-difluorophenyl)boronic acid as starting material. Purified withprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₄H₂₄FN₆OS (M+H)⁺: m/z=463.2; Found: 463.2. ¹H NMR (500MHz, DMSO-d₆) δ 11.22 (s, 1H), 9.33 (d, J=5.0 Hz, 1H), 8.52 (d, J=8.8Hz, 1H), 8.19 (d, J=5.0 Hz, 1H), 8.16 (br s, 3H), 7.95 (d, J=8.8 Hz,1H), 7.50 (td, J=8.0, 5.8 Hz, 1H), 7.28 (m, 2H), 3.70 (s, 1H), 3.65-3.58(m, 2H), 3.52 (q, J=8.4 Hz, 1H), 3.25 (td, J=8.4, 3.8 Hz, 1H), 2.84 (s,3H), 2.30 (s, 3H), 2.12-2.01 (m, 1H), 2.00-1.91 (m, 1H).

Example 3.(R)—N-(4-(3-Aminopyrrolidin-1-yl)-2-methylbenzo[d]thiazol-5-yl)-2-(2-fluoro-6-(trifluoromethyl)phenyl)pyrimidine-4-carboxamide

This compound was prepared according to the procedures described inExample 1, using (2-fluoro-6-(trifluoromethyl)phenyl)boronic acidinstead of (2,6-difluorophenyl)boronic acid as starting material.Purified with prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₄H₂₁F₄N₆OS (M+H)⁺: m/z=517.1; Found: 517.1.

Example 4.(R)—N-(4-(3-Aminopyrrolidin-1-yl)-2-methylbenzo[d]thiazol-5-yl)-2-(2-fluoro-6-methyl-4-((methylamino)methyl)phenyl)pyrimidine-4-carboxamide

This compound was prepared according to the procedures described inExample 1, using tert-butyl(3-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)(methyl)carbamate(Intermediate 3) instead of (2,6-difluorophenyl)boronic acid as startingmaterial. Purified with prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min). LCMS calculated for C₂₆H₂₉FN₇S (M+H)⁺: m/z=506.2; Found: 506.3.¹H NMR (500 MHz, DMSO-d₆) δ 11.19 (s, 1H), 9.33 (d, J=5.0 Hz, 1H), 9.15(br s, 2H), 8.49 (d, J=8.8 Hz, 1H), 8.32 (br s, 2H), 8.20 (d, J=5.0 Hz,1H), 7.94 (d, J=8.8 Hz, 1H), 7.42 (d, J=10.1 Hz, 1H), 7.38 (s, 1H), 4.24(s, 2H), 3.73-3.66 (m, 1H), 3.65-3.59 (m, 2H), 3.53 (q, J=8.4 Hz, 1H),3.26 (td, J=8.4, 3.8 Hz, 1H), 2.84 (s, 3H), 2.64 (s, 3H), 2.31 (s, 3H),2.14-1.94 (m, 2H).

Example 5.(S)—N-(4-(3-Aminopyrrolidin-1-yl)-7-chloro-2-methylbenzo[d]thiazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Step 1. (S)-tert-Butyl1-(7-chloro-2-methyl-5-nitrobenzo[d]thiazol-4-yl)pyrrolidin-3-ylcarbamate

A mixture of (S)-tert-butyl1-(2-methyl-5-nitrobenzo[d]thiazol-4-yl)pyrrolidin-3-ylcarbamate(Intermediate 5, 50 mg, 0.13 mmol), N-chlorosuccinimide (27 mg, 0.20mmol), and DMF (1 mL) was heated to 60° C. for 3 h. The reaction mixturewas cooled to r.t., and water was added to precipitate the product. Thesolid was collected via filtration, washed with water, and dissolved inCH₂Cl₂. The resulting solution was then dried over MgSO₄ andconcentrated. The crude product obtained was used directly in the nextstep without further purification. LCMS calculated for C₁₇H₂₂ClN₄O₄S(M+H)⁺: m/z=413.1; Found: 413.1.

Step 2. (S)-tert-Butyl1-(5-amino-7-chloro-2-methylbenzo[d]thiazol-4-yl)pyrrolidin-3-ylcarbamate

A mixture of tert-butyl(S)-(1-(7-chloro-2-methyl-5-nitrobenzo[d]thiazol-4-yl)pyrrolidin-3-yl)carbamate(from step 1), iron (44.3 mg, 0.793 mmol), ammonium chloride (56.5 mg,1.06 mmol), THF (2 mL), MeOH (2 mL), and water (2 mL) was stirred at 60°C. for 1 hr. After cooling to r.t., water and NaOH (1 mL of 50% aq.soln) were added and the mixture was extracted with EtOAc and CH₂Cl₂.The combined organic phases were washed with saturated aqueous NaClsolution, dried over MgSO₄, and concentrated. The crude product obtainedwas used directly in the next step without further purification. LCMScalculated for C₁₇H₂₄CN₄O₂S (M+H)⁺: m/z=383.1; Found: 383.1.

Step 3.(S)—N-(4-(3-Aminopyrrolidin-1-yl)-7-chloro-2-methylbenzo[d]thiazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

HATU (50.2 mg, 0.132 mmol) was added to a mixture of (S)-tert-butyl1-(5-amino-7-chloro-2-methylbenzo[d]thiazol-4-yl)pyrrolidin-3-ylcarbamate(from step 2), 2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxylic acid(Intermediate 4, 32.8 mg, 0.132 mmol), triethylamine (13 mg, 0.13 mmol)in DMF (1 mL) and the reaction mixture was stirred at 50° C. for 1 hr.After cooling to r.t., water was added and the precipitated product wascollected via filtration, washed with water, and air dried. The solidresidue was then dissolved in TFA and CH₂Cl₂ and stirred at 50° C. for30 minutes. The mixture was then diluted with acetonitrile and purifiedwith prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₄H₂₃ClFN₆O₂S (M+H)⁺: m/z=513.1; Found: 513.2.

Example 6.(S)—N-(4-(3-Aminopyrrolidin-1-yl)-7-bromo-2-methylbenzo[d]thiazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Step 1. (S)-tert-Butyl1-(5-amino-7-bromo-2-methylbenzo[d]thiazol-4-yl)pyrrolidin-3-ylcarbamate

A mixture of tert-butyl(S)-(1-(7-bromo-2-methyl-5-nitrobenzo[d]thiazol-4-yl)pyrrolidin-3-yl)carbamate(Intermediate 6, 34.6 mg, 0.076 mmol), iron (25.3 mg, 0.454 mmol),ammonium chloride (32.4 mg, 0.605 mmol), THE (2 ml), MeOH (2 mL), andwater (2 mL) was stirred at 60° C. for 1 hr. After cooling to r.t.,water and NaOH (1 mL of 50% aq. soln) were added, and the reaction wasextracted with EtOAc and CH₂Cl₂. The combined organic phases were washedwith saturated aqueous NaCl solution, dried over MgSO₄, andconcentrated. The crude product obtained was used directly in the nextstep without further purification. LCMS calculated for C₁₇H₂₄BrN₄O₂S(M+H)⁺: m/z=427.1; Found: 427.0.

Step 2.(S)—N-(4-(3-Aminopyrrolidin-1-yl)-7-bromo-2-methylbenzo[d]thiazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

HATU (28.8 mg, 0.076 mmol) was added to a mixture of (S)-tert-butyl1-(5-amino-7-bromo-2-methylbenzo[d]thiazol-4-yl)pyrrolidin-3-ylcarbamate(from step 2), 2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxylic acid(Intermediate 4, 18.8 mg, 0.076 mmol), and triethylamine (8 mg, 0.08mmol) in DMF (1 mL) and the reaction mixture was stirred at 50° C. for 1hr. After cooling to r.t., water was added and the precipitated productwas collected via filtration, washed with water, and air dried. Thesolid residue was then dissolved in TFA and CH₂Cl₂ and stirred at 50° C.for 30 minutes. The mixture was then diluted with acetonitrile andpurified with prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₄H₂₃BrFN₆O₂S (M+H)⁺: m/z=557.1; Found: 557.2.

Example 7.(S)—N-(4-(3-Aminopyrrolidin-1-yl)-2,7-dimethylbenzo[d]thiazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Step 1. (S)-tert-butyl1-(5-amino-2,7-dimethylbenzo[d]thiazol-4-yl)pyrrolidin-3-ylcarbamate

A mixture of tert-butyl(S)-(1-(7-bromo-2-methyl-5-nitrobenzo[d]thiazol-4-yl)pyrrolidin-3-yl)carbamate(52 mg, 0.114 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (71.4mg, 0.569 mmol), XPhos Pd G2 (8.14 mg, 0.011 mmol), potassium phosphatetribasic (48.2 mg, 0.227 mmol), 1,4-dioxane (1 mL), and water (0.1 mL)was purged under nitrogen, sealed, and stirred at 80° C. for 6 hrs.After cooling to r.t., water was added and the precipitated product wascollected via filtration, washed with water and dissolved in CH₂Cl₂,dried over MgSO₄, and the solvents were evaporated under vacuum. Thecrude residue was treated with iron (38.1 mg, 0.682 mmol), ammoniumchloride (48.7 mg, 0.910 mmol), THE (2 ml), MeOH (2 mL), and water (2mL) and the mixture was stirred at 60° C. for 1 hr. After cooling tor.t., water and NaOH (1 mL of 50% aq. soln) were added, and the reactionwas extracted with EtOAc and CH₂Cl₂. The combined organic phases werewashed with saturated aqueous NaCl solution, dried over MgSO₄, andconcentrated. The crude product obtained was used directly in the nextstep without further purification. LCMS calculated for C₁₈H₂₇N₄O₂S(M+H)⁺: m/z=363.2; Found: 363.1.

Step 2. (S)—N-(4-(3-Aminopyrrolidin-1-yl)-2,7-dimethylbenzo[d]thiazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

HATU (43.2 mg, 0.114 mmol) was added to a mixture of (S)-tert-butyl1-(5-amino-2,7-dimethylbenzo[d]thiazol-4-yl)pyrrolidin-3-ylcarbamate(from step 1), 2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxylic acid(Intermediate 4, 28.2 mg, 0.114 mmol), and triethylamine (12 mg) in DMF(1 mL) and the reaction mixture was stirred at 50° C. for 1 hr. Aftercooling to r.t., water was added and the precipitated product wascollected via filtration, washed with water, dissolved in CH₂Cl₂, driedover MgSO₄, and concentrated. The crude residue was then dissolved inTFA and CH₂Cl₂ and stirred at 50° C. for 30 minutes. The mixture wasthen diluted with acetonitrile and purified with prep-LCMS (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%TFA, at flow rate of 60 mL/min). LCMS calculated for C₂₅H₂₆FN₆O₂S(M+H)⁺: m/z=493.2; Found: 493.2.

Example 8.(S)—N-(4-(3-Aminopyrrolidin-1-yl)-7-cyano-2-methylbenzo[d]thiazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Step 1. (S)-tert-butyl1-(5-amino-7-cyano-2-methylbenzo[d]thiazol-4-yl)pyrrolidin-3-ylcarbamate

A mixture of tert-butyl(S)-(1-(7-bromo-2-methyl-5-nitrobenzo[d]thiazol-4-yl)pyrrolidin-3-yl)carbamate(Intermediate 6, 53 mg, 0.116 mmol), dicyanozinc (68.0 mg, 0.579 mmol),Pd₂(dba)₃ (21.2 mg, 0.023 mmol), Xantphos (46.9 mg, 0.081 mmol), DMF (1ml), and TMEDA (17 μL, 0.116 mmol) was purged under nitrogen, sealed,and stirred at 110° C. overnight. After cooling to r.t. the reactionmixture was filtered over a pad of Celite, and the filter was washedwith CH₂Cl₂ and EtOAc. The filtrate was then diluted with water andextracted with CH₂Cl₂, and the combined organic phases were dried overMgSO₄ and concentrated. The crude residue was treated with iron (38.8mg, 0.695 mmol), ammonium chloride (49.6 mg, 0.927 mmol), THF (2 ml),MeOH (2 mL), and water (2 mL) and the mixture was stirred at 60° C. for1 hr. After cooling to r.t., water and NaOH (1 mL of 50% aq. soln) wereadded, and the reaction was extracted with EtOAc and CH₂Cl₂. Thecombined organic phases were washed with saturated aqueous NaClsolution, dried over MgSO₄, and concentrated. The crude product obtainedwas used directly in the next step without further purification. LCMScalculated for C₁₈H₂₄N₅O₂S (M+H)⁺: m/z=374.2; Found: 374.2.

Step 2.(S)—N-(4-(3-Aminopyrrolidin-1-yl)-7-cyano-2-methylbenzo[d]thiazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

HATU (44.1 mg, 0.116 mmol) was added to a mixture of (S)-tert-butyl1-(5-amino-7-cyano-2-methylbenzo[d]thiazol-4-yl)pyrrolidin-3-ylcarbamate(from step 1), 2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxylic acid(Intermediate 4, 28.8 mg, 0.116 mmol), and triethylamine (12 mg) in DMF(1 mL) and the reaction mixture was stirred at 50° C. for 1 hr. Aftercooling to r.t., water was added and the precipitated product wascollected via filtration, washed with water, dissolved in CH₂Cl₂, driedover MgSO₄, and concentrated. The crude residue was then dissolved inTFA and CH₂Cl₂ and stirred at 50° C. for 30 minutes. The mixture wasthen diluted with acetonitrile and purified with prep-LCMS (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%TFA, at flow rate of 60 mL/min). LCMS calculated for C₂₅H₂₃FN₇O₂S(M+H)⁺: m/z=504.2; Found: 504.2.

Example 9.(S)—N-(4-(2-(Aminomethyl)pyrrolidin-1-yl)-2-(methoxymethyl)benzo[d]thiazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Step 1.(S)-tert-Butyl(1-(2-(methoxymethyl)-5-nitrobenzo[d]thiazol-4-yl)pyrrolidin-2-yl)methylcarbamate

A mixture of tert-butyl(S)-((1-(3-fluoro-2-(2-methoxyacetamido)-6-nitrophenyl)pyrrolidin-2-yl)methyl)carbamate(Intermediate 7, 303 mg, 0.711 mmol) in THF (5 mL) was treated withLawesson's reagent (216 mg, 0.533 mmol), and the reaction mixture waspurged under nitrogen and stirred at 60° C. overnight. After cooling tor.t., the mixture was concentrated under vacuum, and the crude residuewas purified by Biotage Isolera™ LCMS calculated for C₁₉H₂₇N₄O₅S (M+H)⁺:m/z=423.2; Found 423.2.

Step 2.(S)—N-(4-(2-(Aminomethyl)pyrrolidin-1-yl)-2-(methoxymethyl)benzo[d]thiazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

A mixture of tert-butyl(S)-((1-(2-(methoxymethyl)-5-nitrobenzo[d]thiazol-4-yl)pyrrolidin-2-yl)methyl)carbamate(from step 3), iron (238 mg, 4.26 mmol), and ammonium chloride (304 mg,5.68 mmol) in THE (5 mL), water (5 mL) and methanol (5 mL) was stirredat 60° C. for 1 hr. After cooling to r.t., the reaction mixture wasfiltered through a plug of Celite, diluted with water, and extractedwith CH₂Cl₂. The combined organic phases were dried over MgSO₄, and thesolvents were evaporated under vacuum. The crude residue was thentreated with HATU (270 mg, 0.711 mmol),2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxylic acid (Intermediate4, 176 mg, 0.711 mmol), DMF (1 mL), and triethylamine (0.1 mL, 0.717mmol), and the reaction mixture was stirred at 50° C. for 30 minutes.After cooling to r.t., water was added and the precipitated product wascollected via filtration, washed with water, and air dried. The solidresidue was then dissolved in TFA and CH₂Cl₂ and the resultant solutionwas stirred at 50° C. for 30 minutes. The mixture was then diluted withacetonitrile and purified with prep-LCMS (XBridge C18 column, elutingwith a gradient of acetonitrile/water containing 0.1% TFA, at flow rateof 60 mL/min). LCMS calculated for C₂₆H₂₈FN₆O₃S (M+H)⁺: m/z=523.2; Found523.2.

Example 10.(S)—N-(4-(2-(Aminomethyl)pyrrolidin-1-yl)-2-(2-methoxyethyl)benzo[d]thiazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

This compound was prepared according to the procedures described inExample 9, using (S)-tert-butyl(1-(3-fluoro-2-(3-methoxypropanamido)-6-nitrophenyl)pyrrolidin-2-yl)methylcarbamate(Intermediate 8) instead of (S)-tert-butyl(1-(3-fluoro-2-(2-methoxyacetamido)-6-nitrophenyl)pyrrolidin-2-yl)methylcarbamate(Intermediate 7) as starting material. Purified with prep-LCMS (XBridgeC18 column, eluting with a gradient of acetonitrile/water containing0.1% TFA, at flow rate of 60 mL/min). LCMS calculated for C₂₇H₃₀FN₆O₃S(M+H)⁺: m/z=537.2; Found: 537.2. ¹H NMR (500 MHz, DMSO-d₆) δ 11.54 (s,1H), 9.30 (d, J=5.0 Hz, 1H), 8.57 (d, J=8.8 Hz, 1H), 8.17 (d, J=5.0 Hz,1H), 8.00 (d, J=8.8 Hz, 1H), 7.66 (t, J=5.6 Hz, 3H), 7.59 (td, J=8.5,6.9 Hz, 1H), 7.10 (d, J=8.5 Hz, 1H), 7.03 (m, 1H), 4.14-4.06 (m, 1H),3.84-3.73 (m, 5H), 3.35 (t, J=6.1 Hz, 2H), 3.31 (s, 3H), 3.26-3.16 (m,2H), 2.64-2.54 (m, 1H), 2.46-2.37 (m, 1H), 2.30-2.21 (m, 1H), 2.00-1.90(m, 1H), 1.73-1.57 (m, 2H).

Example 11.N-(4-((2S,4R)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-2-methylbenzo[d]thiazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Step 1: tert-Butyl(3R,5S)-1-(5-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)-2-methylbenzo[d]thiazol-4-yl)-5-(hydroxymethyl)pyrrolidin-3-ylcarbamate

HATU (485 mg, 1.276 mmol) was added to a solution of tert-butyl((3R,5S)-1-(5-amino-2-methylbenzo[d]thiazol-4-yl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate(0.4874 g, 1.288 mmol, 39.4% yield) (from Intermediate 13, step 2),2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxylic acid (Intermediate4, 317 mg, 1.276 mmol), and triethylamine (0.3 mL, 2.15 mmol) in DMF (1mL). The reaction mixture was stirred at 50° C. for 30 minutes. Aftercooling to r.t., water was added and the precipitated product wascollected via filtration, washed with water, and air dried. Theresultant crude product was purified by Biotage Isolera™. LCMScalculated for C₃₀H₃₄FN₆O₅S (M+H)⁺: m/z=609.2; Found 609.2.

Step 2:N-(4-((2S,4R)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-2-methylbenzo[d]thiazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

A mixture of tert-butyl((3R,5S)-1-(5-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)-2-methylbenzo[d]thiazol-4-yl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate(from step 1) in CH₂Cl₂ (2 mL) was treated with TFA (2 mL) and thereaction mixture was stirred at r.t. for 1 hr. The mixture was thendiluted with acetonitrile and purified with prep-LCMS (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%TFA, at flow rate of 60 mL/min). LCMS calculated for C₂₅H₂₆FN₆O₃S(M+H)⁺: m/z=509.2; Found 509.3. ¹H NMR (600 MHz, DMSO-d₆) δ 11.51 (s,1H), 9.29 (d, J=5.0 Hz, 1H), 8.56 (d, J=8.8 Hz, 1H), 8.35 (s, 3H), 8.16(d, J=5.0 Hz, 1H), 8.00 (d, J=8.8 Hz, 1H), 7.58 (td, J=8.5, 6.8 Hz, 1H),7.09 (d, J=8.5 Hz, 1H), 7.04 (t, J=8.8 Hz, 1H), 3.99 (qd, J=7.4, 5.0 Hz,1H), 3.79 (s, 3H), 3.63 (m, 1H), 3.51 (dd, J=10.3, 5.7 Hz, 1H), 3.35(dd, J=10.3, 5.0 Hz, 1H), 3.19 (dd, J=10.5, 4.9 Hz, 1H), 3.12 (dd,J=10.5, 7.4 Hz, 1H), 2.86 (s, 3H), 2.28 (m, 1H), 1.77 (dt, J=13.3, 7.4Hz, 1H).

Example 12.N-(4-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-2-ethylbenzo[d]thiazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Step 1. tert-Butyl(3S,5S)-1-(2-ethyl-5-nitrobenzo[d]thiazol-4-yl)-5-(hydroxymethyl)pyrrolidin-3-ylcarbamate

A mixture of 4-chloro-2-ethyl-5-nitrobenzo[d]thiazole (Intermediate 11,42 mg, 0.17 mmol) and tert-butyl((3S,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate (44.9 mg, 0.208mmol), and triethylamine (0.07 mL, 0.5 mmol) in DMSO (1 mL) was stirredat 120° C. for 2 hrs. After cooling to r.t., water was added and theprecipitated product was washed with water and air dried. The resultantcrude product was used in the next step without further purification.LCMS calculated for C₁₉H₂₇N₄O₅S (M+H)⁺. m/z=423.2; Found 423.1.

Step 2.tert-Butyl(3S,5S)-1-(5-amino-2-ethylbenzo[d]thiazol-4-yl)-5-(hydroxymethyl)pyrrolidin-3-ylcarbamate

A mixture of tert-butyl(3S,5S)-1-(2-ethyl-5-nitrobenzo[d]thiazol-4-yl)-5-(hydroxymethyl)pyrrolidin-3-ylcarbamate(from step 1), iron (58.0 mg, 1.04 mmol), and ammonium chloride (74.1mg, 1.39 mmol) in THE (2 mL), MeOH (2 mL), and water (2 mL) was stirredat 60° C. for 1 hr. After cooling to r.t., the reaction mixture wasfiltered through a plug of Celite, diluted with water, and extractedwith CH₂Cl₂. The combined organic phases were dried over MgSO₄ andconcentrated under vacuum. The obtained crude product was used in thenext step without further purification. LCMS calculated for C₁₉H₂₉N₄O₃S(M+H)⁺: m/z=393.2; Found 393.2.

Step 3:N-(4-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-2-ethylbenzo[d]thiazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

HATU (65.8 mg, 0.173 mmol) was added to a solution of tert-butyl(3S,5S)-1-(5-amino-2-ethylbenzo[d]thiazol-4-yl)-5-(hydroxymethyl)pyrrolidin-3-ylcarbamate(from step 2), 2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxylic acid(Intermediate 4, 43.0 mg, 0.173 mmol), and triethylamine (0.07 mL, 0.502mmol) in DMF (1 mL). The reaction mixture was stirred at 50° C. for 30minutes before water was added and the precipitated product wascollected via filtration, washed with water, and air dried. The solidresidue was then dissolved in TFA and CH₂Cl₂ and the resultant solutionwas stirred at 50° C. for 30 minutes. The mixture was then diluted withacetonitrile and purified with prep-LCMS (XBridge C18 column, elutingwith a gradient of acetonitrile/water containing 0.1% TFA, at flow rateof 60 mL/min). LCMS calculated for C₂₆H₂₈FN₆O₃S (M+H)⁺: m/z=523.2; Found523.2.

Example 13.N-(4-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-2-isopropylbenzo[d]thiazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

This compound was prepared according to the procedures described inExample 12, using 4-chloro-2-isopropyl-5-nitrobenzo[d]thiazole(Intermediate 12) instead of 4-chloro-2-ethyl-5-nitrobenzo[d]thiazole(Intermediate 11) as starting material. Purified with prep-LCMS (XBridgeC18 column, eluting with a gradient of acetonitrile/water containing0.1% TFA, at flow rate of 60 mL/min). LCMS calculated for C₂₇H₃₀FN₆O₃S(M+H)⁺: m/z=537.2; Found: 537.1.

Example 14.N-(4-((2S,4R)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-2-methylbenzo[d]thiazol-5-yl)-2-(2-carbamoyl-6-methoxyphenyl)pyrimidine-4-carboxamide

A mixture of tert-butyl((3R,5S)-1-(5-(2-chloropyrimidine-4-carboxamido)-2-methylbenzo[d]thiazol-4-yl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate(Intermediate 13, 76 mg, 0.146 mmol), (2-cyano-6-methoxyphenyl)boronicacid (15.55 mg, 0.088 mmol), XPhos Pd G2 (57.6 mg, 0.073 mmol),potassium phosphate tribasic (62.2 mg, 0.293 mmol), 1,4-dioxane (1 mL),and water (0.2 mL) was purged under nitrogen and stirred at 80° C. for 2hrs. After cooling to r.t., the reaction mixture was concentrated andTFA (1 mL) was added and the resulting mixture was stirred at r.t. for30 minutes. The reaction mixture was then diluted with acetonitrile andpurified with prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₆H₂₈N₇O₄S (M+H)⁺: m/z=534.2; Found: 534.2.

Example 15.N-(4-((2S,4R)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-2-methylbenzo[d]thiazol-5-yl)-2-(2-fluoro-6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrimidine-4-carboxamide

A mixture of tert-butyl((3R,5S)-1-(5-(2-chloropyrimidine-4-carboxamido)-2-methylbenzo[d]thiazol-4-yl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate(Intermediate 13, 76 mg, 0.146 mmol), XPhos Pd G2 (57.6 mg, 0.073 mmol),1,4-dioxane (1 mL), and water (0.2 mL) was purged under nitrogen andstirred at 80° C. for 1 hr. After cooling to r.t.,(3-bromo-2-fluoro-6-methoxyphenyl)boronic acid (21.9 mg, 0.088 mmol),additional XPhos Pd G2 (57.6 mg, 0.073 mmol), and potassium phosphatetribasic (62.2 mg, 0.293 mmol) were added, the reaction mixture wassparged with nitrogen and stirred at 80° C. for 30 minutes before1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(30.5 mg, 0.146 mmol) was added, and the reaction mixture was stirred at80° C. for an additional 1 hr. After cooling to r.t., the reactionmixture was concentrated and TFA (1 mL) was added and the resultingmixture was stirred at r.t. for 30 minutes. The reaction mixture wasthen diluted with acetonitrile and purified with prep-LCMS (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%TFA, at flow rate of 60 mL/min). The fractions containing product werethen concentrated and purified with prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% NH₄OH, atflow rate of 60 m/min). LCMS calculated for C₂₉H₃₀FN₈O₃S (M+H)⁺:m/z=589.2; Found: 589.2.

Example 16.N-(4-((2S,4R)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-2-methylbenzo[d]thiazol-5-yl)-2-(2,3-difluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

HATU (15 mg, 0.040 mmol) was added to a solution of tert-butyl((3R,5S)-1-(5-amino-2-methylbenzo[d]thiazol-4-yl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate(Intermediate 10, 15 mg, 0.040 mmol),2-(2,3-difluoro-6-methoxyphenyl)pyrimidine-4-carboxylic acid(Intermediate 14, 10.6 mg, 0.040 mmol) and triethylamine (0.01 mL, 0.072mmol) in DMF (1 mL). The reaction mixture was stirred at 50° C. for 30minutes. After cooling to r.t., water was added and the precipitatedproduct was collected via filtration, washed with water, and air dried.The solid residue was then dissolved in TFA and the resultant solutionwas stirred at r.t. for 30 minutes. The reaction mixture was thendiluted with acetonitrile and purified with prep-LCMS (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%TFA, at flow rate of 60 mL/min). LCMS calculated for C₂₅H₂₅F₂N₆O₃S(M+H)⁺: m/z=527.2; Found: 527.1. ¹H NMR (500 MHz, DMSO-d₆) δ 11.46 (s,1H), 9.32 (d, J=5.0 Hz, 1H), 8.56 (d, J=8.8 Hz, 1H), 8.26 (br s, 3H),8.20 (d, J=5.0 Hz, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.64 (q, J=9.4 Hz, 1H),7.07 (ddd, J=9.4, 3.6, 1.7 Hz, 1H), 4.44 (t, J=5.0 Hz, 1H), 4.00 (qd,J=7.3, 5.0 Hz, 1H), 3.78 (s, 3H), 3.70-3.60 (m, 1H), 3.55 (dd, J=10.4,5.8 Hz, 1H), 3.24-3.17 (m, 1H), 3.17-3.11 (m, 1H), 2.87 (s, 3H),2.34-2.26 (m, 1H), 1.84-1.75 (m, 1H).

Example 17.N-(4-((2S,4R)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-2-methylbenzo[d]thiazol-5-yl)-2-(3-cyano-2-fluoro-6-(methoxy-d₃)phenyl)pyrimidine-4-carboxamide

This compound was prepared according to the procedures described inExample 16, using2-(3-cyano-2-fluoro-6-(methoxy-d₃)phenyl)pyrimidine-4-carboxylic acid(Intermediate 15) instead of2-(2,3-difluoro-6-methoxyphenyl)pyrimidine-4-carboxylic acid(Intermediate 14) as starting material. Purified with prep-LCMS (XBridgeC18 column, eluting with a gradient of acetonitrile/water containing0.1% TFA, at flow rate of 60 mL/min). LCMS calculated for C₂₆H₂₂D₃FN₇O₃S(M+H)⁺: m/z=537.2; Found: 537.2.

Example 18.2-(2-Fluoro-6-methoxyphenyl)-N-(4-((2S,4R)-2-(hydroxymethyl)-4-(isopropylamino)pyrrolidin-1-yl)-2-methylbenzo[d]thiazol-5-yl)pyrimidine-4-carboxamide

A solution ofN-(4-((2S,4R)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)-2-methylbenzo[d]thiazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide(Example 11, 57 mg, 0.11 mmol) in 1,2-DCE (1 mL) was treated withacetone (0.02 mL, 0.27 mmol), acetic acid (0.02 mL, 0.35 mmol), andsodium triacetoxyborohydride (47.5 mg, 0.224 mmol). The reaction mixturewas then stirred at r.t. overnight. Water was then added and thereaction mixture was concentrated under vacuum, diluted withacetonitrile, and purified with prep-LCMS (XBridge C18 column, elutingwith a gradient of acetonitrile/water containing 0.1% TFA, at flow rateof 60 mL/min). LCMS calculated for C₂H₃₂FN₆O₃S (M+H)⁺: m/z=551.2; Found:551.2. ¹H NMR (600 MHz, DMSO-d₆) δ 11.46 (s, 1H), 9.29 (d, J=5.0 Hz,1H), 8.97 (br d, J=79.1 Hz, 2H), 8.60 (d, J=8.8 Hz, 1H), 8.17 (d, J=5.0Hz, 1H), 7.99 (d, J=8.8 Hz, 1H), 7.57 (td, J=8.5, 6.9 Hz, 1H), 7.09 (d,J=8.5 Hz, 1H), 7.02 (t, J=8.8 Hz, 1H), 4.49 (t, J=5.2 Hz, 1H), 4.12 (tt,J=8.0, 5.2 Hz, 1H), 3.78 (s, 3H), 3.55-3.46 (m, 2H), 3.46-3.39 (m, 1H),3.21-3.11 (m, 3H), 2.84 (s, 3H), 2.33-2.25 (m, 1H), 1.99-1.91 (m, 1H),1.13 (dd, J=22.8, 6.4 Hz, 6H).

Example 19.2-(2-Fluoro-6-methoxyphenyl)-N-(4-((2S,4R)-2-(hydroxymethyl)-4-(tetrahydro-2H-pyran-4-ylamino)pyrrolidin-1-yl)-2-methylbenzo[d]thiazol-5-yl)pyrimidine-4-carboxamide

This compound was prepared according to the procedures described inExample 18, using tetrahydro-4H-pyran-4-one instead of acetone asstarting material. Purified with prep-LCMS (XBridge C18 column, elutingwith a gradient of acetonitrile/water containing 0.1% TFA, at flow rateof 60 mL/min). LCMS calculated for C₃H₃₄FN₆O₄S (M+H)⁺: m/z=593.2; Found:593.2.

Example 20.N-(4-((2S,4R)-4-Acetamido-2-(hydroxymethyl)pyrrolidin-1-yl)-2-methylbenzo[d]thiazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

A solution ofN-(4-((2S,4R)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)-2-methylbenzo[d]thiazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide(Example 11, 38 mg, 0.075 mmol) in DMF (1 mL) was treated with a 0.1 Mstock solution of acetic acid (0.75 mL, 0.075 mmol) in THF, HATU (28.4mg, 0.075 mmol), and triethylamine (0.04 mL, 0.287 mmol). The reactionmixture was stirred at 50° C. for 30 minutes. After cooling to r.t., thereaction mixture was concentrated slightly, water was added and theprecipitated product was collected via filtration, washed with water,and air dried. The crude material was then dissolved in acetonitrile andpurified with prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₇H₂₈FN₆O₄S (M+H)⁺: m/z=551.2; Found: 551.2.

Example 21.2-(2-Fluoro-6-methoxyphenyl)-N-(4-((2S,4R)-2-(hydroxymethyl)-4-(methylsulfonamido)pyrrolidin-1-yl)-2-methylbenzo[d]thiazol-5-yl)pyrimidine-4-carboxamide

A solution ofN-(4-((2S,4R)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)-2-methylbenzo[d]thiazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide(Example11, 38 mg, 0.075 mmol) and triethylamine (8 mg, 0.079 mmol) in anhydrousTHF (2 mL) was treated with a 0.1 M solution of methanesulfonyl chloride(0.75 mL, 0.075 mmol) in anhydrous THF. The reaction mixture was stirredat r.t. for 15 minutes. The reaction was then treated with water, andthe resulting mixture was diluted with acetonitrile and purified withprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₆H₂₈FN₆O₅S₂ (M+H)⁺: m/z=587.2; Found: 587.1. ¹H NMR(600 MHz, DMSO-d₆) δ 11.64 (s, 1H), 9.28 (d, J=5.0 Hz, 1H), 8.58 (d,J=8.8 Hz, 1H), 8.16 (d, J=5.0 Hz, 1H), 7.97 (d, J=8.8 Hz, 1H), 7.91 (d,J=7.9 Hz, 1H), 7.57 (td, J=8.4, 6.8 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H),7.02 (t, J=8.8 Hz, 1H), 4.31 (br s, 1H), 3.93-3.85 (m, 1H), 3.75-3.83(m, 4H), 3.44 (dd, J=9.5, 5.8 Hz, 1H), 3.21 (dd, J=9.5, 5.8 Hz, 1H),3.19-3.08 (m, 2H), 2.86 (s, 6H), 2.18-2.10 (m, 1H), 1.75-1.67 (m, 1H).

Example 22.N-(4-((1R,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-methylbenzo[d]thiazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

This compound was prepared according to the procedures described inExample 11, using (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane instead oftert-butyl ((3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate asstarting material. LCMS calculated for C₂₅H₂₃FN₅O₃S (M+H)⁺: m/z=492.2;Found: 492.2.

Example 23.N-(4-((2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)-2-methylbenzo[d]thiazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

This compound was prepared according to the procedures described inExample 11, using tert-butyl((3S,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate instead oftert-butyl ((3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate asstarting material. LCMS calculated for C₂₅H₂₆FN₆O₃S (M+H)⁺: m/z=509.2;Found: 509.2.

Example 24.2-(2-Fluoro-6-methoxyphenyl)-N-(2-methyl-4-(methyl((1-methylpyrrolidin-3-yl)methyl)amino)benzo[d]thiazol-5-yl)pyrimidine-4-carboxamide

This compound was prepared according to the procedures described inExample 11, using N-methyl-1-(1-methylpyrrolidin-3-yl)methanamineinstead of tert-butyl((3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate as startingmaterial. LCMS calculated for C₂₇H₃₀FN₆O₂S (M+H)⁺: m/z=521.2; Found:521.3.

Example 25.2-(2-Fluoro-6-methoxyphenyl)-N-(2-methyl-4-((1R,4R)-5-(morpholine-4-carbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)benzo[d]thiazol-5-yl)pyrimidine-4-carboxamide

Step 1.N-(4-((1R,4R)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-2-methylbenzo[d]thiazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

This compound was prepared according to the procedures described inExample 11, using tert-butyl(1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate instead oftert-butyl ((3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate asstarting material. LCMS calculated for C₂₅H₂₄FN₆O₂S (M+H)⁺: m/z=491.2;Found: 491.3.

Step 2.2-(2-Fluoro-6-methoxyphenyl)-N-(2-methyl-4-((R,4R)-5-(morpholine-4-carbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)benzo[d]thiazol-5-yl)pyrimidine-4-carboxamide

Triphosgene (3.6 mg, 0.012 mmol) was added to a solution ofN-(4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-methylbenzo[d]thiazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide(6 mg, 0.012 mmol) and triethylamine (3.4 μL, 0.024 mmol) in THF (1 mL).After the reaction mixture was stirred at r.t. for 20 minutes,morpholine (1.1 mg, 0.012 mmol) was added and the reaction mixture wasstirred for another 20 minutes. Then, the reaction was diluted withCH₃CN and purified with prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min). LCMS calculated for C₃₀H₃₁FN₇O₄S (M+H)⁺: m/z=604.2; Found:604.3.

Example 26.(S)—N-(4-(3-(aminomethyl)morpholino)-2-methylbenzo[d]thiazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

This compound was prepared according to the procedures described inExample 11, using tert-butyl (S)-(morpholin-3-ylmethyl)carbamate insteadof tert-butyl ((3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate asstarting material. LCMS calculated for C₂₅H₂₆FN₆O₃S (M+H)⁺: m/z=509.2;Found: 509.2.

Example 27.(R)-2-(2-Fluoro-6-methoxyphenyl)-N-(2-methyl-4-(methyl(piperidin-3-yl)amino)benzo[d]thiazol-5-yl)pyrimidine-4-carboxamide

This compound was prepared according to the procedures described inExample 11, using tert-butyl (R)-3-(methylamino)piperidine-1-carboxylateinstead of tert-butyl((3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate as startingmaterial. LCMS calculated for C₂₆H₂₈FN₆O₂S (M+H)⁺: m/z=507.2; Found:507.2.

Example 28.2-(2-Fluoro-6-methoxyphenyl)-N-(2-methyl-4-(octahydro-1H-pyrrolo[2,3-c]pyridin-1-yl)benzo[d]thiazol-5-yl)pyrimidine-4-carboxamide

This compound was prepared according to the procedures described inExample 11, using tert-butyloctahydro-6H-pyrrolo[2,3-c]pyridine-6-carboxylate instead of tert-butyl((3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate as startingmaterial. LCMS calculated for C₂₇H₂₈FN₆O₂S (M+H)⁺: m/z=519.2; Found:519.2.

Example29.2-(2-Fluoro-6-methoxyphenyl)-N-(2-methyl-4-(3-(pyridin-2-yl)pyrrolidin-1-yl)benzo[d]thiazol-5-yl)pyrimidine-4-carboxamide

This compound was prepared according to the procedures described inExample 11, using 2-(pyrrolidin-3-yl)pyridine instead of tert-butyl((3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate as startingmaterial. LCMS calculated for C₂₉H₂₆FN₆O₂S (M+H)⁺: m/z=541.2; Found:541.2.

Example 30.(S)—N-(4-(4,4-Difluoro-2-(hydroxymethyl)pyrrolidin-1-yl)-2-methylbenzo[d]thiazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

This compound was prepared according to the procedures described inExample 11, using (S)-(4,4-difluoropyrrolidin-2-yl)methanol instead oftert-butyl ((3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate asstarting material. LCMS calculated for C₂₅H₂₃F₃N₅O₃S (M+H)⁺: m/z=530.2;Found: 530.2.

Example 31.N-(4-((1S,4S)-2,5-Diazabicyclo[2.2.2]octan-2-yl)-2-methylbenzo[d]thiazol-5-yl)-2-(2,6-difluorophenyl)pyrimidine-4-carboxamide

This compound was prepared according to the procedures described inExample 11, using tert-butyl(1S,4S)-5-(5-amino-2-methylbenzo[d]thiazol-4-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate(Intermediate 17) instead of tert-butyl((3R,5S)-1-(5-amino-2-methylbenzo[d]thiazol-4-yl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate(Intermediate 10) and 2-(2,6-difluorophenyl)pyrimidine-4-carboxylic acid(Intermediate 16) instead of2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxylic acid (Intermediate4) as starting materials. LCMS calculated for C₂₅H₂₃F₂N₆OS (M+H)⁺:m/z=493.2; Found: 493.2.

Example 32.N-(4-((2S,4R)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)-2-((dimethylamino)methyl)benzo[d]thiazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

Step 1. tert-Butyl((3R,5S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-1-(2-((dimethylamino)methyl)-5-nitrobenzo[d]thiazol-4-yl)pyrrolidin-3-yl)carbamate

A solution of tert-butyl((3R,5S)-1-(2-bromo-5-nitrobenzo[d]thiazol-4-yl)-5-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidin-3-yl)carbamate(Intermediate 18, 60 mg, 0.102 mmol) in 1,4-dioxane (0.67 mL) and water(0.168 mL) was treated with potassium ((dimethylamino)methyl)trifluoroborate (33 mg, 0.204 mmol) followed by RuPhos Pd G2 (7.9 mg,10.2 μmol). Nitrogen was bubbled through the reaction mixture for 5minutes and then the reaction was heated at 100° C. for 1 hr. After thistime it was cooled to r.t. and concentrated to dryness. The residue waspurified by silica gel chromatography using 0-10% methanol in CH₂Cl₂with 1% triethylamine as additive. LCMS calculated for C₂₆H₄₄N₅O₅SSi(M+H)⁺. m/z=566.2; found 566.2.

Step 2. tert-Butyl((3R,5S)-1-(5-amino-2-((dimethylamino)methyl)benzo[d]thiazol-4-yl)-5-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidin-3-yl)carbamate

The intermediate from Step 1 was dissolved in methanol (2 mL) andtreated with Pd/C (10 mg) and the mixture was stirred for 1 hr at r.t.under a hydrogen atmosphere. After this time it was filtered. Thefiltrate was concentrated to dryness to afford the crude intermediatewhich was used for next step without further purification. LCMScalculated for C₂₆H₄₆N₅O₃SSi (M+H)⁺: m/z=536.2; found 536.2.

Step 3.N-(4-((2S,4R)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)-2-((dimethylamino)methyl)benzo[d]thiazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide

The intermediate from Step 2 was dissolved in DMF (1 mL) and treatedwith 2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxylic acid (12 mg,0.051 mmol), followed by addition of DIPEA (0.054 mL, 0.31 mmol) andHATU (116 mg, 0.306 mmol). The resulting solution was stirred at r.t.for 1 hr then diluted with ethyl acetate and washed with water andsaturated aqueous NaCl solution. The organic phase was dried over MgSO₄,filtered and then concentrated to dryness. The residue was dissolved in1 mL of methanol, then HCl (0.5 mL, 4.0 M in dioxane) was added and thereaction was stirred at r.t. for another 2 hrs. After this time it wasdiluted with methanol, filtered and purified with prep-LCMS (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%TFA, at flow rate of 60 mL/min). LCMS calculated for C₂₇H₃₁FN₇O₃S(M+H)⁺: m/z=552.2; found 552.2.

Example A. HPK1 Kinase Binding Assay

A stock solution of 1 mM test compound was prepared in DMSO. Thecompound plate was prepared by 3-fold and 11-point serial dilutions. 0.1μL of the compound in DMSO was transferred from the compound plate tothe white 384 well polystyrene plates. The assay buffer contained 50 mMHEPES, pH 7.5, 0.01% Tween-20, 5 mM MgCl₂, 0.01% BSA, and 5 mM DTT. 5 μLof 4 nM active HPK1 (SignalChem M23-11G) prepared in the buffer wasadded to the plate. The enzyme concentration given was based on thegiven stock concentration reported by the vender. 5 μl of 18 nM tracer222 (ThermoFisher PV6121) and 4 nM LanthaScreen Eu-Anti GST antibody(ThermoFisher PV5595) were added. After one hour incubation at 25° C.,the plates were read on a PHERAstar FS plate reader (BMG Labtech). K_(i)values were determined.

Compounds of the present disclosure, as exemplified in Examples, showedthe K_(i) values in the following ranges: +=K_(i)≤100 nM; ++=100nM<K_(i)≤500 nM; +++=500 nM<K_(i)≤5000 nM.

TABLE 1 Example K_(i), nM 1 + 2 + 3 + 4 + 5 + 6 + 7 + 8 + 9 + 10 + 11 +12 + 13 + 14 ++ 15 + 16 + 17 + 18 + 19 + 20 + 21 + 22 + 23 + 24 + 25 +26 + 27 + 28 + 29 + 30 + 31 + 32 +

Example B. p-SLP76S376 HTRF Assay

One or more compounds of the invention can be tested using thep-SLP76S376 HTRF assay described as follows. Jurkat cells (cultured inRPMI1640 media with 10% FBS) are collected and centrifuged, followed byresuspension in appropriate media at 3×10⁶ cells/mL. The Jurkat cells(35 μL) are dispensed into each well in a 384 well plate. Test compoundsare diluted with cell culture media for 40-fold dilution (adding 39 μLcell culture media into 1 μL compound). The Jurkat cells in the wellplate are treated with the test compounds at various concentrations(adding 5 ul diluted compound into 35 μL Jurkat cells and starting from3 uM with 1:3 dilution) for 1 hour at 37° C., 5% CO₂), followed bytreatment with anti-CD3 (5 μg/mL, OKT3 clone) for 30 min. A 1:25dilution of 100× blocking reagent (from p-SLP76 ser376HTRF kit) with4×Lysis Buffer(LB) is prepared and 15 μL of the 4×LB buffer withblocking reagent is added into each well and incubated at roomtemperature for 45 mins with gentle shaking. The cell lysate (16 μL) isadded into a Greiner white plate, treated with p-SLP76 ser376HTRFreagents (2 μL donor, 2 ul acceptor) and incubated at 4° C. forovernight. The homogeneous time resolved fluorescence (HTRF) is measuredon a PHERAstar plate reader the next day. IC₅₀ determination isperformed by fitting the curve of percent inhibition versus the log ofthe inhibitor concentration using the GraphPad Prism 5.0 software.

Example C. Isolation of CD4+ or CD8+ T Cells and Cytokine Measurement

Blood samples are collected from healthy donors. CD4+ or CD8+ T cellsare isolated by negative selection using CD4+ or CD8+ enrichment kits(lifetech, USA). The purity of the isolated CD4+ or CD8+ T cells isdetermined by flow cytometry and is routinely >80%. Cells are culturedin RPMI 1640 supplemented with 10% FCS, glutamine and antibiotics(Invitrogen Life Technologies, USA). For cytokine measurement, Jurkatcells or primary CD4+ or CD8+ T cells are plated at 200 k cells/well andare stimulated for 24 h with anti-CD3/anti-CD28 beads in the presence orabsence of testing compounds at various concentrations. 16 μL ofsupernatants are then transferred to a white detection plate andanalyzed using the human IL2 or IFNγ assay kits (Cisbio).

Example D. Treg Assay

One or more compounds can be tested using the Regulatory T-cellproliferation assay described as following. Primary CD4+/CD25− T-cellsand CD4+/CD25+ regulatory T-cells are isolated from human donatedPeripheral Blood Mononuclear Cells, using an isolated kit from ThermoFisher Scientific (11363D). CD4+/CD25− T-cells are labeled with CFSE(Thermo Fisher Scientific, C34554) following the protocol provided bythe vendor. CFSE labeled T-cells and CD4+/CD25+ regulatory T-cells arere-suspended at the concentration of 1×106 cells/mL in RPMI-1640 medium.100 μL of CFSE-labeled T-cells are mixed with or without 50 μL ofCD4+/CD25+ regulatory T-cells, treated with 5 μl of anti-CD3/CD28 beads(Thermo Fisher Scientific, 11132D) and various concentrations ofcompounds diluted in 50 μl of RPMI-1640 medium. Mixed populations ofcells are cultured for 5 days (37° C., 5% CO₂) and proliferation ofCFSE-labeled T-cells is analyzed by BD LSRFortessa X-20 using FITCchannel on the 5th day.

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including withoutlimitation all patent, patent applications, and publications, cited inthe present application is incorporated herein by reference in itsentirety.

1-41. (canceled)
 42. A method for treating a cancer in a patient, saidmethod comprising: administering to the patient a therapeuticallyeffective amount of a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: A is N; Cy^(B)is selected from C₅₋₁₀ cycloalkyl, C₆₋₁₀ aryl, and 5-6 memberedheteroaryl; wherein the 5-6 membered heteroaryl each has at least onering-forming carbon atom and 1, 2 or 3 ring-forming heteroatomsindependently selected from N, O, and S: wherein the N and S areoptionally oxidized; wherein a ring-forming carbon atom of 5-6 memberedheteroaryl is optionally substituted by oxo to form a carbonyl group;and wherein the C₅₋₁₀ cycloalkyl, C₆₋₁₀ aryl and 5-6 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁷; R¹ is selected from Cy¹, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, SR^(a1), C(O)R^(b1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c10)C(O)NR^(c1)R^(d1), C(═NR^(e1))R^(b1),C(═NOR^(a1))R^(b1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),S(O)₂NR^(c1)R^(d1), and BR^(h1)R^(i1); wherein said C₂₋₆ alkenyl andC₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹⁰; R² is selected from H, D,C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, halo, CN, NO₂,OR^(f2), SR^(f2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),OC(O)R^(b2), OC(O)NR^(c2)R^(d2), NR^(j2)R^(k2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), C(═NR^(e2))R^(b2),C(═NOR^(a2))R^(b2), C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2),NR^(c2)S(O)₂NR^(c2)R^(d2) S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2)S(O)₂NR^(c2)R^(d2), and BR^(h2)R^(i2); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹³; R³ is selected fromH, D, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl, 4-6 membered heterocycloalkyl, halo, CN, NO₂, OR^(a3),SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3),OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3) S(O)₂NR^(c3)R^(d3), and BR^(h3)R^(i3);wherein said C₁₋₆ alkyl, C₂₋₆alkenyl and C₂₋₆ alkynyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g); R⁴ is selected from H, D, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, 4-6 memberedheterocycloalkyl, halo, CN, NO₂, OR^(a4), SR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4),NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4),NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4),S(O)₂R^(b4)S(O)₂NR^(c4)R^(d4), and BR^(h4)R^(i4); wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R⁹; R⁵ isselected from H, D, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, halo, CN, NO₂, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)OR^(a5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)S(O)R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O₂NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)R^(b5),S(O)₂NR^(c5)R^(d5), and BR^(h5)R^(i5); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, and C₁₋₆ alkynyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R^(g); R⁶ is selected fromH, D, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN NO₂,OR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6),OC(O)NR^(c6)R^(d6), NR^(c6)C(O)R^(b6) NR^(c6)C(O)OR^(a6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)S(O)R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6), S(O)₂R^(b6),S(O)₂NR^(c6)R^(d6), and BR^(h6)R^(i6): wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R^(g); each R⁷ isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 memberedheteroaryl-C₁₋₃ alkylene, halo, D, CN, NO₂, OR^(a7), SR^(a7),C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7), OC(O)R^(b7),OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)OR^(a7), NR^(c7)C(O)NR^(c7)R^(d7), C(═NR^(c7))R^(b7),C(═NOR^(a7))R^(b7), C(═NR^(c7))NR^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c7)R^(d7), NR^(c7)S(O)R^(b7), NR^(c7)S(O)₂R^(b7),NR^(c7)S(O)₂NR^(c7)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7), S(O)₂R^(b7)S(O)₂NR^(c7)R^(d7), and BR^(h7)R^(i7); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene,4-10 membered heterocycloalkyl-C₁₋₃ alkylene C₆₋₁₀ aryl-C₁₋₃ alkylene,and 5-10 membered heteroaryl-C₁₋₃ alkylene are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR⁸; each R⁸ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₃₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene 4-10 membered heterocycloalkyl-C₁₋₃ alkyleneC₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, OR^(a8), SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8),NR^(c8)R^(d8), NR^(c8)C(O)R^(b8), NR^(c8)C(O)OR^(a8), NR^(b8)S(O)R^(b8),NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), S(O)R^(b8),S(O)NR^(c8)R^(d8), S(O)R^(b8), S(O)₂NR^(c8)R^(d8), and BR^(h8)R^(i8);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene 4-10 membered heterocycloalkyl-C₁₋₃alkylene C₆₋₁₀ aryl-C₁₋₃ alkylene, and 5-10 membered heteroaryl-C₁₋₃alkylene are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁹; each R⁹ is independently selected fromC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, halo, D,CN, OR^(a9), SR^(a9), C(O)R^(b9), C(O)NR^(c9)R^(d9), C(O)OR^(a9),NR^(c9)R^(d9), NR^(c9)C(O)R^(b9); NR^(c9)C(O)OR^(a9), NR^(c9)S(O)R^(b9),NR^(c9)S(O)₂R^(b9), NR^(c9)S(O)₂NR^(c9)R^(d9), S(O)R^(b9),S(O)NR^(c9)R^(d9), S(O)₂R^(b9), and S(O)₂NR^(c9)R^(d9); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6membered heteroaryl and 4-7 membered heterocycloalkyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g); Cy¹ is selected from C₃₋₁₂ cycloalkyl, 4-12membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein the 4-12 membered heterocycloalkyl and 5-10 membered heteroaryleach has at least one ring-forming carbon atom and 1, 2, 3, or 4ring-forming heteroatoms independently selected from N, O, and S;wherein the N and S are optionally oxidized; wherein a ring-formingcarbon atom of 5-10 membered heteroaryl and 4-12 memberedheterocycloalkyl is optionally substituted by oxo to form a carbonylgroup; and wherein said C₃₋₁₂ cycloalkyl, 4-12 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁰; each R¹⁰ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, NO₂, OR^(a10), SR^(a10) C(O)R^(b10), C(O)NR^(c10)R^(d10),C(O)OR^(a10), OC(O)R^(b10), OC(O)NR^(c10)R^(d10), NR^(c10)R^(d10),NR^(c10)C(O)R^(b10), NR^(c10) C(O)OR^(a10), NR^(c10)C(O)NR^(c10)R^(d10),C(═NR^(e10))R^(b10), C(═NOR^(a10))R^(b10), C(═NR^(e10))NR^(c10)R^(d10),NR^(c10)C(═NR^(e10))NR^(c10)R^(d10), NR^(c10)S(O)R^(b10), NR^(c10)S(O)R^(b10), NR^(c10)S(Ob)NR^(c10)R^(d10), S(O)R^(b10),S(O)NR^(c10)R^(d10), S(O)²R^(b10), S(O)₂NR^(c10)R^(d10), andBR^(h10)R^(i10); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹¹; each R¹¹ isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 memberedheteroaryl-C₁₋₃ alkylene, halo, D, CN, OR^(a11) SR^(a11), C(O)R^(b11),C(O)NR^(c11)R^(d11), C(O)OR^(a11), NR^(c11)R^(d11), NR^(c11)C(O)R^(b11),NR^(c11)C(O)OR^(a11), NR^(c11)S(O)R^(b11), NR^(c11)S(O)₂R^(b11),NR^(c11)S(O)₂NR^(c11)R^(d11), S(O)R^(b11), S(O)NR^(c11)R^(d11),S(O)₂R^(b11), S(O)₂NR^(c11)R^(d11), and BR^(h11)R^(i11); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹²; each R¹² is independently selected fromC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, 4-7 membered heterocycloalkyl,halo, D, CN, OR^(a12), SR^(a12), C(O)R^(b12), C(O)NR^(c12)R^(d12),C(O)OR^(a12), NR^(c12)R^(d12), NR^(c12)C(O)R^(b12),NR^(c10)C(O)OR^(a12), NR^(c12)S(O)R^(b12), NR^(c12)S(O)₂R^(b12),NR^(e12)S(O)₂NR^(c2)R^(d12), S(O)R^(b12), S(O)NR^(c12)R^(d12),S(O)₂R^(b12) S(O)₂NR^(c12)R^(d12), and BR^(h12)R^(i12); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, and 4-7 membered heterocycloalkyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g); each R¹³ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, D, CN, NO₂, OR^(a13),SR^(a13), C(O)R^(b13), C(O)NR^(c13)R^(d13), C(O)OR^(a13), OC(O)R^(b13),OC(O)N^(c13)R^(d13), NR^(c13)R^(d13), NR^(c13)C(O)R^(b13),NR^(c13)C(O)OR^(a13), NR^(c13)C(O)NR^(c13)R^(d13), C(═NR^(e13))R^(b13),C(═NOR^(a13))R^(b13), C(═NR^(e13))NR^(c13)R^(d13),NR¹³C(═NR^(e13))NR^(c13)R^(d13), NR^(c13)S(O)R^(b13)NR^(c13)S(O)₂R^(b13), NR^(c13)S(O)₂NR^(c13)R^(d13), S(O)R^(b13),S(O)NR^(c13)R^(d13), S(O)₂R^(b13), S(O)₂NR^(c13)R^(d13) andBR^(h13)R^(i13); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl, are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g2); each R^(a1), R^(c1), and R^(d1) isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl, and 5-10 membered heteroaryl: wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl, and 5-10 membered heteroaryl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R¹⁰; or anyR^(c1) and R^(d1) attached to the same N atom, together with the N atomto which they are attached, form a 4-10 membered heterocycloalkyl groupoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁰; each R^(b1) is independently selected from C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl:wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹⁰; each R^(e1) is independently selectedfrom H, CN, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylaminosulfonyl, carbamyl,C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl, aminosulfonyl, C₂₋₆alkylaminosulfonyl, and di(C₁₋₆ alkyl)aminosulfonyl; each R^(h1) andR^(i1) is independently selected from OH and C₁₋₆alkoxy; or any R^(h1)and R^(i1) attached to the same B atom are C₂₋₃ dialkoxy and togetherwith the B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl; each R^(a2),R^(c2), and R^(d2) is independently selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl: wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g); or any R^(c2) and R^(d2) attached to the same Natom, together with the N atom to which they are attached, form a 4-10membered heterocycloalkyl group optionally substituted with 1, 2, 3, or4 substituents independently selected from R^(g); each R^(b2) isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,and 5-10 membered heteroaryl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,and 5-10 membered heteroaryl are each optionally substituted with 1, 2,3, or 4 substituents independently selected from R^(g); each R^(f2),R^(j2), and R^(k2) is independently selected from H, C₁₋₆alkyl, C₁₋₆alkenyl, C₂₋₆ alkynyl and C₁₋₆haloalkyl; wherein said C₁₋₆ alkyl, C₁₋₆alkenyl, and C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R^(g2); each R^(e2) isindependently selected from H, CN, C₁₋₆ alkyl C₁₋₆ haloalkyl, C₁₋₆alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₂₋₆ alkylaminosulfonyl, and di(C₁₋₆alkyl)aminosulfonyl; each R^(h2) and R^(i2) is independently selectedfrom OH and C₁₋₆ alkoxy; or any R^(h2) and R^(i2) attached to the same Batom are C₂₋₃ dialkoxy and together with the B atom to which they areattached, form a 5- or 6-membered heterocycloalkyl group optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromC₁₋₆ alkyl; each R^(a3), R^(c3), and R^(d3) is independently selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g); each R^(b3) is independently selected from C₁₋₆alkyl, C₂₋₆ alkenyl, C₁₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g); eachR^(h3) and R^(i3) is independently selected from OH and C₁₋₆ alkoxy; orany R^(h3) and R^(i3) attached to the same B atom are C₂₋₃ dialkoxy andtogether with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3,or 4 substituents independently selected from C₁₋₆ alkyl; each R^(a4),R^(c4), and R^(d4) is independently selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₁₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R^(g); each R^(b4) isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, andC₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g); each R^(h4) and R^(i4) isindependently selected from OH and C₁₋₆ alkoxy; or any R^(h4) and R^(i4)attached to the same B atom are C₂₋₃ dialkoxy and together with the Batom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl; each R^(a5) isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₁₋₆ alkenyl, and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g); each R^(c5) and R^(d5) isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, andC₁₋₆haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g); each R^(b5) is independently selectedfrom C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(g); each R^(h5) and R^(i5) is independently selected from OH andC₁₋₆alkoxy; or any R^(h5) and R^(i5) attached to the same B atom areC₂₋₃ dialkoxy and together with the B atom to which they are attached,form a 5- or 6-membered heterocycloalkyl group optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from C₁₋₆ alkyl;each R^(a6), R^(c6), and R^(d6) is independently selected from H, C₁₋₆alkyl, C₁₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g); eachR^(b6) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, andC₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g); each R^(h6) and R^(i6)is independently selected from OH and C₁₋₆alkoxy; or any R^(h6) andR^(i6) attached to the same B atom are C₂₋₃ dialkoxy and together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl; each R^(a7),R^(c7), and R^(d7) is independently selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl; wherein saidC₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R₈; or any R^(c7) and R^(d7) attached to the same N atom,together with the N atom to which they are attached, form a 4-, 5-, 6-or 7-membered heterocycloalkyl group optionally substituted with 1, 2,3, or 4 substituents independently selected from R₈; each R^(b7) isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,and 5-10 membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl, and 5-10 membered heteroaryl are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R₈; each R^(e7)is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl,aminosulfonyl, C₁₋₆alkylaminosulfonyl, and di(C₁₋₆alkyl)aminosulfonyl;each R^(h7) and R^(i7) is independently selected from OH and C₁₋₆alkoxy;or any R^(h7) and R^(i7) attached to the same B atom are C₂₋₃ dialkoxyand together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3,or 4 substituents independently selected from C₁₋₆ alkyl; each R^(a8),R_(c8), and R^(d8) is independently selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6membered heteroaryl and 4-7 membered heterocycloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl, and 4-7 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR⁹; or any R^(c8) and R^(d8) attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R⁹; each R^(b8) isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7membered heterocycloalkyl; wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7membered heterocycloalkyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R⁹; each R^(h8) and R^(i8)is independently selected from OH and C₁₋₆ alkoxy; or any R^(h8) andR^(i8) attached to the same B atom are C₂₋₃ dialkoxy and together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl; each R^(a9),R^(c9), and R^(d9) is independently selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R^(g); each R^(b9) isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆ alkynyl, andC₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g); each R^(a10), R^(c10), and R^(d10) isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl, and 5-10 membered heteroaryl; wherein said C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl, and 5-10 membered heteroaryl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R¹¹; or anyR^(c10) and R^(d10) attached to the same N atom, together with the Natom to which they are attached, form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹; each R^(b10) isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,and 5-10 membered heteroaryl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,and 5-10 membered heteroaryl are each optionally substituted with 1, 2,3, or 4 substituents independently selected from R¹¹; each R^(e10) isindependently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl,di(C₁₋₆)alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl, anddi(C₁₋₆ alkyl)aminosulfonyl; each R^(h10) and R^(i10) is independentlyselected from OH and C₁₋₆ alkoxy; or any R^(h10) and R^(i10) attached tothe same B atom are C₂₋₃ dialkoxy and together with the B atom to whichthey are attached, form a 5- or 6-membered heterocycloalkyl groupoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from C₁₋₆ alkyl; each R^(a11), R^(c11), and R^(d11) isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7membered heterocycloalkyl; wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7membered heterocycloalkyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹²; or any R^(c11) andR^(d11) attached to the same N atom, together with the N atom to whichthey are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2 or 3 substituents independentlyselected from R¹²; each R^(b11) is independently selected from C₁₋₆alkyl, C₂₋₆ alkenyl, C₃₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl:wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹²; each R^(h11) and R^(i11) isindependently selected from OH and C₁₋₆ alkoxy; or any R^(h11) andR^(i11) attached to the same B atom are C₂₋₃ dialkoxy and together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl; each R^(a12),R^(c12) and R^(d12) is independently selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R^(g); each R^(b12) isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl andC₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g); each R^(h12) and R^(i12) isindependently selected from OH and C₁₋₆ alkoxy; or any R^(h12) andR^(i12) attached to the same B atom are C₂₋₃ dialkoxy and together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl; each R^(a13),R^(c13), and R^(d13) is independently selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g); each R^(b13) is independently selected from C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10 memberedheteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g); each R^(e13) isindependently selected from H, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl, and di(C₁₋₆alkyllaminosulfonyl; each R^(h13) and R^(i13) is independently selectedfrom OH and C₁₋₆ alkoxy; or any R^(h13) and R^(i13) attached to the sameB atom are C₂₋₃ dialkoxy and together with the B atom to which they areattached, form a 5- or 6-membered heterocycloalkyl group optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromC₁₋₆ alkyl; each R^(g) is independently selected from OH, NO₂, CN, halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkyl-C₁₋₂ alkylene, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, C₁₋₃alkoxy-C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkoxy, HO—C₁₋₃ alkoxy, HO—C₁₋₃alkyl, cyano-C₁₋₃ alkyl, H₂N—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkylcarbamyl,carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino; and each R^(g2) is independently selected fromOH, NO₂, CN, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₃alkoxy-C₁₋₃ alkylC₁₋₃alkoxy-C₁₋₃ alkoxy, HO—C₁₋₃ alkoxy, HO—C₁₋₃ alkyl, cyano-C₁₋₃ alkyl,H₂N—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, thio,C₁₋₆alkylthio, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl, C₁₋₆alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆alkoxycarbonyl, C₁₋₆ alkylcarbonylamino, C₁₋₆ alkylsulfonylamino,aminosulfonyl, C₁₋₆ alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl,aminosulfonylamino, C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₆alkylaminocarbonylamino, and di(C₁₋₆ alkyl)aminocarbonylamino.
 43. Themethod of claim 42, wherein the cancer is selected from breast cancer,colorectal cancer, lung cancer, ovarian cancer, and pancreatic cancer.44. The method of claim 42, wherein the cancer is selected from breastcancer, colorectal cancer, lung cancer, ovarian cancer, pancreaticcancer, prostate cancer, colon cancer, esophageal cancer, endometrialcancer, uterine cancer, renal cancer, hepatic cancer, gastric cancer,cancers of the head and neck, thyroid cancer, glioblastoma, sarcoma, andbladder cancer.
 45. The method of claim 42, wherein the cancer isselected from acute lymphoblastic leukemia (ALL), acute myelogenousleukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocyticleukemia (CLL), chronic myelogenous leukemia (CML), diffuse large B-celllymphoma (DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma, Hodgkinlymphoma, primary myelofibrosis (PMF), polycythemia vera (PV), essentialthrombocytosis (ET), myelodysplasia syndrome (MDS), T-cell acutelymphoblastic lymphoma (T-ALL), multiple myeloma, cutaneous T-celllymphoma, Waldenstrom's Macroglubulinemia, hairy cell lymphoma, chronicmyelogenic lymphoma and Burkitt's lymphoma.
 46. The method of claim 42,wherein Cy^(B) is selected from 5-6 membered heteroaryl and C₆₋₁₀ aryl;wherein the 5-6 membered heteroaryl and C₆₋₁₀ aryl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR⁷.
 47. The method of claim 42, wherein Cy^(B) is C₆₋₁₀ aryl optionallysubstituted with 1, 2, or 3 substituents independently selected from R⁷.48. The method of claim 42, wherein Cy^(B) is phenyl optionallysubstituted with 1, 2, or 3 substituents independently selected from R⁷.49. The method of claim 42, wherein each R⁷ is independently selectedfrom C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, halo, D, CN, OR^(a7), SR^(a7), C(O)R^(b7),C(O)NR^(c7)R^(d7), C(O)OR^(a7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7), andNR^(c7)C(O)OR^(a7), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁸.
 50. The method of claim 42,wherein each R⁷ is independently selected from C₁₋₆ alkyl, C₁₋₆haloalkyl, 5-6 membered heteroaryl, halo, CN, OR^(a7), andC(O)NR^(c7)R^(d7), wherein said C₁₋₆ alkyl and 5-6 membered heteroarylare each optionally substituted with 1, 2, or 3 substituentsindependently selected from R⁸.
 51. The method of claim 42, whereinCy^(B) is phenyl substituted with 1, 2, or 3 substituents selected fromF, CN, OCH₃, CH₃, CD₃, CF₃, C(O)NH₂, and 1-methyl-1H-pyrazol-4-yl. 52.The method of claim 42, wherein R¹ is selected from Cy¹, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, SR^(a1), C(O)R^(b1), C(O)OR^(a1),NR^(c1)R^(d1), and NR^(c1)C(O)R^(b1); wherein said C₂₋₆ alkenyl and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹⁰.
 53. The method of claim 42, wherein R¹is selected from Cy¹ and NR^(c1)R^(d1).
 54. The method of claim 42,wherein R¹ is Cy¹.
 55. The method of claim 42, wherein Cy¹ is selectedfrom 4-12 membered heterocycloalkyl and C₆₋₁₀ aryl; wherein the 4-12membered heterocycloalkyl has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of 4-12 membered heterocycloalkyl is optionallysubstituted by oxo to form a carbonyl group; and wherein the 4-12membered heterocycloalkyl and C₆₋₁₀ aryl are each optionally substitutedwith 1, 2, or 3 substituents independently selected from R¹⁰.
 56. Themethod of claim 42, wherein Cy¹ is 4-10 membered heterocycloalkyl;wherein the 4-10 membered heterocycloalkyl has at least one ring-formingcarbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independentlyselected from N, O, and S; wherein the N and S are optionally oxidized;wherein a ring-forming carbon atom of 4-10 membered heterocycloalkyl isoptionally substituted by oxo to form a carbonyl group; and wherein the4-10 membered heterocycloalkyl is optionally substituted with 1, 2, or 3substituents independently selected from R¹⁰.
 57. The method of claim42, wherein Cy¹ is selected from pyrrolidinyl, morpholino,oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl,octahydro-1H-pyrrolo[2,3-c]pyridinyl, and2,5-diazabicyclo[2.2.2]octanyl, wherein said pyrrolidinyl, morpholino,oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl,octahydro-1H-pyrrolo[2,3-c]pyridinyl, and 2,5-diazabicyclo[2.2.2]octanylare each optionally substituted with 1, 2, or 3 substituentsindependently selected from R¹⁰.
 58. The method of claim 42, whereineach R¹⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, D, CN,OR^(a10), SR^(a10), C(O)R^(b10), C(O)NR^(c10)R^(d10), NR^(c10)R^(d10),NR^(c10)C(O)R^(b10), NR^(c10)C(O)OR^(a10), and NR^(c10)S(O)₂R^(b10);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroarylare each optionally substituted with 1, 2, or 3 substituentsindependently selected from R¹¹.
 59. The method of claim 42, whereineach R¹⁰ is independently selected from C₁₋₆ alkyl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, halo, C(O)R^(b10),NR^(c10)R^(d10) NR^(c10)C(O)R^(b10), and NR^(c10)S(O)₂R^(b10), whereinsaid C₁₋₆ alkyl and 5-10 membered heteroayl are each optionallysubstituted with 1 or 2 substituents independently selected from R¹¹.60. The method of claim 42, wherein each R¹¹ is independently selectedfrom C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, D,CN, OR^(a11), and NR^(c11)R^(d11).
 61. The method of claim 42, whereineach R¹¹ is independently selected from C₁₋₆ alkyl, OR^(a11) andNR^(c11)R^(d11).
 62. The method of claim 42, wherein R¹ isNR^(c1)R^(d1).
 63. The method of claim 42, wherein R¹ is selected from3-aminopyrrolidin-1-yl, 2-(aminomethyl)pyrrolidin-1-yl,4-amino-2-(hydroxymethyl)pyrrolidin-1-yl,2-(hydroxymethyl)-4-(isopropylamino)pyrrolidin-1-yl,2-(hydroxymethyl)-4-(tetrahydro-2H-pyran-4-ylamino)pyrrolidin-1-yl,4-acetamido-2-(hydroxymethyl)pyrrolidin-1-yl,2-(hydroxymethyl)-4-(methylsulfonamido)pyrrolidin-1-yl,2-oxa-5-azabicyclo[2.2.1]heptan-5-yl,methyl((1-methylpyrrolidin-3-yl)methyl)amino,2,5-diazabicyclo[2.2.1]heptan-2-yl, 3-(aminomethyl)morpholino,methyl(piperidin-3-yl)amino, octahydro-1H-pyrrolo[2,3-c]pyridin-1-yl,3-(pyridin-2-yl)pyrrolidin-1-yl,4,4-difluoro-2-(hydroxymethyl)pyrrolidin-1-yl, and2,5-diazabicyclo[2.2.2]octan-2-yl.
 64. The method of claim 42, whereinR² is selected from H, D, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, halo, CN, OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2),C(O)OR^(a2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), and S(O)₂NR^(c2)R^(d2);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from R¹³.
 65. The method of claim 42, wherein R² is C₁₋₆ alkyloptionally substituted with 1, 2, or 3 substituents independentlyselected from R¹³.
 66. The method of claim 42, wherein each R¹³ isindependently selected from halo, D, CN, OR^(a13), C(O)R^(b13),C(O)NR^(c13)R^(d13), NR^(c13)R^(d13) and NR^(c13)C(O)R^(b13).
 67. Themethod of claim 42, wherein each R¹³ is independently selected fromOR^(a13), and NR^(c13)R^(d13).
 68. The method of claim 42, wherein R² isselected from CH₃, CH₂CH₃, CH₂OCH₃, CH₂CH₂OCH₃, CH(CH₃)₂, andCH₂N(CH₃)₂.
 69. The method of claim 42, wherein R³ is selected from H,C₁₋₆ alkyl, halo, and CN.
 70. The method of claim 42, wherein R⁴ is H.71. The method of claim 42, wherein R⁵ is H.
 72. The method of claim 42,wherein R⁶ is H.
 73. The method of claim 42, wherein the compound hasFormula III:

or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, or 3.74. The method of claim 42, wherein the compound has Formula IIIa:

or a pharmaceutically acceptable salt thereof.
 75. The method of claim42, wherein the compound has Formula IV:

or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, or 3.76. The method of claim 42, wherein the compound has Formula V:

or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, or 3.77. The method of claim 42, wherein: A is N; Cy^(B) is selected fromC₆₋₁₀ aryl optionally substituted with 1, 2, 3 or 4 substituentsindependently selected from R⁷; R¹ is selected from Cy¹ andNR^(c1)R^(d1); R² is C₁₋₆ alkyl optionally substituted with 1, 2, 3, or4 substituents independently selected from R¹³; R³ and R⁴ are eachindependently selected from H, D, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, andCN; wherein said C₁₋₆ alkyl is optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g); R⁵ is selected from H,D, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, and CN; R⁶ is selected from H, D,C₁₋₆ alkyl, C₁₋₆ haloalkyl, and CN; each R⁷ is independently selectedfrom C₁₋₆ alkyl, C₁₋₆ haloalkyl, 5-10 membered heteroaryl, halo, D, CN,OR^(a7), SR^(a7), C(O)NR^(c7)R^(d7), NR^(c7)R^(d7), andNR^(c7)C(O)R^(b7); wherein said C₁₋₆ alkyl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁸; each R⁸ is independently selected fromC₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, D, CN, OR^(a8), and NR^(c8)R^(d8); Cy¹is selected from 4-12 membered heterocycloalkyl, and 5-10 memberedheteroaryl; wherein the 4-12 membered heterocycloalkyl and 5-10 memberedheteroaryl each has at least one ring-forming carbon atom and 1, 2, 3,or 4 ring-forming heteroatoms independently selected from N, O, and S;wherein the N and S are optionally oxidized; wherein a ring-formingcarbon atom of 5-10 membered heteroaryl and 4-12 memberedheterocycloalkyl is optionally substituted by oxo to form a carbonylgroup; and wherein the 4-12 membered heterocycloalkyl, and 5-10 memberedheteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹⁰; each R¹⁰ is independentlyselected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, D, CN,OR^(a10), SR^(a10), C(O)NR^(c10)R^(d10), NR^(c10)R^(d10),NR^(c10)C(O)R^(b10), and NR^(c10)S(O)₂R^(b10); wherein said C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹; each R¹¹ is independentlyselected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, D, CN, OR^(a11) andNR^(c11)R^(d11); each R¹³ is independently selected from halo, D, CN,OR^(a13), and NR^(c13)R^(d13); each R^(c1) and R^(d1) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl and 4-10membered heterocycloalkyl; wherein said C₁₋₆ alkyl, C₃₋₁₀cycloalkyl and4-10 membered heterocycloalkyl, are each optionally substituted with 1,2, 3, or 4 substituents independently selected from R¹⁰; or any R^(c1)and R^(d1) attached to the same N atom, together with the N atom towhich they are attached, form a 4-10 membered heterocycloalkyl groupoptionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹⁰; each R^(a7), R^(c7) and R^(d7) is independentlyselected from H and C₁₋₆ alkyl; wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR; each R^(a8), R^(c8) and R^(d8) is independently selected from H andC₁₋₆ alkyl; each R^(a10), R^(c10), and R^(d10) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl; wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, and 4-10membered heterocycloalkyl, are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹¹; or any R^(c10) andR^(d10) attached to the same N atom, together with the N atom to whichthey are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹; each R^(b10) is independently selectedfrom C₁₋₆ alkyl; each R^(a11), R^(c11), and R^(d11) is independentlyselected from H and C₁₋₆ alkyl; each R^(a13), R^(c13), and R^(d13) isindependently selected from H and C₁₋₆ alkyl; and each R^(g) isindependently selected from OH, CN, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, amino, C₁₋₆ alkylamino, and di(C₁₋₆alkyl)amino.
 78. The method of claim 42, wherein: A is N; Cy^(B) isselected from C₆₋₁₀ aryl optionally substituted with 1, 2, 3 or 4substituents independently selected from R⁷; R¹ is selected from Cy¹,and NR^(c1)R^(d1); R² is C₁₋₆ alkyl optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹³; R³ and R⁴ are eachindependently selected from H, D, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo andCN; R⁵ is H; R⁶ is H; each R⁷ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, 5-10 membered heteroaryl, halo, D, CN, OR^(a7),C(O)NR^(c7)R^(d7) and NR^(c7)R^(d7); wherein said C₁₋₆ alkyl and 5-10membered heteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁸; each R⁸ is independentlyselected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, D, CN, OR^(a8), andNR^(c8)R^(d8); Cy¹ is selected from 4-12 membered heterocycloalkyl;wherein the 4-12 membered heterocycloalkyl has at least one ring-formingcarbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independentlyselected from N, O, and S; wherein the N and S are optionally oxidized;wherein a ring-forming carbon atom is optionally substituted by oxo toform a carbonyl group; and wherein the 4-12 membered heterocycloalkyl isoptionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹⁰; each R¹⁰ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, 4-10 membered heterocycloalkyl, 5-10 memberedheteroaryl, halo, D, CN, OR^(a1), C(O)NR^(c10)R^(d10), NR^(c10)R^(d10),NR^(c10)C(O)R^(b10) and NR^(c10)S(O)₂R^(b10); wherein said C₁₋₆ alkyl,4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹¹; each R¹¹ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, halo, D, CN, OR^(a11), and NR^(c11)R^(d11); each R¹³ isindependently selected from halo, D, CN, OR^(a13), and NR^(c13)R^(d13);each R^(c1) and R^(d1) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, and 4-10 membered heterocycloalkyl; wherein said C₁₋₆alkyl and 4-10 membered heterocycloalkyl, are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹⁰; each R^(a7), R^(c7), and R^(d7) is independently selected from Hand C₁₋₆ alkyl; wherein said C₁₋₆ alkyl is optionally substituted with1, 2, 3, or 4 substituents independently selected from R⁸; each R^(a8),R^(c8), and R^(d8) is independently selected from H and C₁₋₆ alkyl; eachR^(a10), R^(c10), and R^(d10) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, and 4-10 membered heterocycloalkyl; wherein saidC₁₋₆ alkyl and 4-10 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹¹; or any R^(c10) and R^(d10) attached to the same N atom, togetherwith the N atom to which they are attached, form a 4-, 5-, 6-, or7-membered heterocycloalkyl group optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹¹; each R^(b10) isindependently selected from C₁₋₆ alkyl; each R^(a11), R^(c11), andR^(d11) is independently selected from H and C₁₋₆ alkyl; and eachR^(a13), R^(c13), and R^(d13) is independently selected from H and C₁₋₆alkyl.
 79. The method of claim 42, wherein the compound is selectedfrom:(R)—N-(4-(3-Aminopyrrolidin-1-yl)-2-methylbenzo[d]thiazol-5-yl)-2-(2,6-difluorophenyl)pyrimidine-4-carboxamide;(R)—N-(4-(3-Aminopyrrolidin-1-yl)-2-methylbenzo[d]thiazol-5-yl)-2-(2-fluoro-6-methylphenyl)pyrimidine-4-carboxamide;(R)—N-(4-(3-Aminopyrrolidin-1-yl)-2-methylbenzo[d]thiazol-5-yl)-2-(2-fluoro-6-(trifluoromethyl)phenyl)pyrimidine-4-carboxamide;(R)—N-(4-(3-Aminopyrrolidin-1-yl)-2-methylbenzo[d]thiazol-5-yl)-2-(2-fluoro-6-methyl-4-((methylamino)methyl)phenyl)pyrimidine-4-carboxamide;(S)—N-(4-(3-Aminopyrrolidin-1-yl)-7-chloro-2-methylbenzo[d]thiazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;(S)—N-(4-(3-Aminopyrrolidin-1-yl)-7-bromo-2-methylbenzo[d]thiazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;(S)—N-(4-(3-Aminopyrrolidin-1-yl)-2,7-dimethylbenzo[d]thiazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;(S)—N-(4-(3-Aminopyrrolidin-1-yl)-7-cyano-2-methylbenzo[d]thiazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;(S)—N-(4-(2-(Aminomethyl)pyrrolidin-1-yl)-2-(methoxymethyl)benzo[d]thiazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;(S)—N-(4-(2-(Aminomethyl)pyrrolidin-1-yl)-2-(2-methoxyethyl)benzo[d]thiazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;N-(4-((2S,4R)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-2-methylbenzo[d]thiazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;N-(4-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-2-ethylbenzo[d]thiazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;N-(4-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-2-isopropylbenzo[d]thiazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;N-(4-((2S,4R)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-2-methylbenzo[d]thiazol-5-yl)-2-(2-carbamoyl-6-methoxyphenyl)pyrimidine-4-carboxamide;N-(4-((2S,4R)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-2-methylbenzo[d]thiazol-5-yl)-2-(2-fluoro-6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrimidine-4-carboxamide;N-(4-((2S,4R)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-2-methylbenzo[d]thiazol-5-yl)-2-(2,3-difluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;N-(4-((2S,4R)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-2-methylbenzo[d]thiazol-5-yl)-2-(3-cyano-2-fluoro-6-(methoxy-d)phenyl)pyrimidine-4-carboxamide;2-(2-Fluoro-6-methoxyphenyl)-N-(4-((2S,4R)-2-(hydroxymethyl)-4-(isopropylamino)pyrrolidin-1-yl)-2-methylbenzo[d]thiazol-5-yl)pyrimidine-4-carboxamide;2-(2-Fluoro-6-methoxyphenyl)-N-(4-((2S,4R)-2-(hydroxymethyl)-4-(tetrahydro-2H-pyran-4-ylamino)pyrrolidin-1-yl)-2-methylbenzo[d]thiazol-5-yl)pyrimidine-4-carboxamide;N-(4-((2S,4R)-4-Acetamido-2-(hydroxymethyl)pyrrolidin-1-yl)-2-methylbenzo[d]thiazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;2-(2-Fluoro-6-methoxyphenyl)-N-(4-((2S,4R)-2-(hydroxymethyl)-4-(methylsulfonamido)pyrrolidin-1-yl)-2-methylbenzo[d]thiazol-5-yl)pyrimidine-4-carboxamide;N-(4-((1R,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-methylbenzo[d]thiazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;N-(4-((2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)-2-methylbenzo[d]thiazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;2-(2-Fluoro-6-methoxyphenyl)-N-(2-methyl-4-(methyl((1-methylpyrrolidin-3-yl)methyl)amino)benzo[d]thiazol-5-yl)pyrimidine-4-carboxamide;2-(2-Fluoro-6-methoxyphenyl)-N-(2-methyl-4-((1R,4R)-5-(morpholine-4-carbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)benzo[d]thiazol-5-yl)pyrimidine-4-carboxamide;(S)—N-(4-(3-(aminomethyl)morpholino)-2-methylbenzo[d]thiazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;(R)-2-(2-Fluoro-6-methoxyphenyl)-N-(2-methyl-4-(methyl(piperidin-3-yl)amino)benzo[d]thiazol-5-yl)pyrimidine-4-carboxamide;2-(2-Fluoro-6-methoxyphenyl)-N-(2-methyl-4-(octahydro-1H-pyrrolo[2,3-c]pyridin-1-yl)benzo[d]thiazol-5-yl)pyrimidine-4-carboxamide;2-(2-Fluoro-6-methoxyphenyl)-N-(2-methyl-4-(3-(pyridin-2-yl)pyrrolidin-1-yl)benzo[d]thiazol-5-yl)pyrimidine-4-carboxamide;(S)—N-(4-(4,4-Difluoro-2-(hydroxymethyl)pyrrolidin-1-yl)-2-methylbenzo[d]thiazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;N-(4-((1S,4S)-2,5-Diazabicyclo[2.2.2]octan-2-yl)-2-methylbenzo[d]thiazol-5-yl)-2-(2,6-difluorophenyl)pyrimidine-4-carboxamide;andN-(4-((2S,4R)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)-2-((dimethylamino)methyl)benzo[d]thiazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide;or a pharmaceutically acceptable salt thereof.
 80. The method of claim42, wherein the compound isN-(4-((2S,4R)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)-2-methylbenzo[d]thiazol-5-yl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide,or a pharmaceutically acceptable salt thereof.